U.S. patent number 8,741,932 [Application Number 13/508,135] was granted by the patent office on 2014-06-03 for imidazopyridine derivatives.
This patent grant is currently assigned to Piramal Enterprises Limited. The grantee listed for this patent is Mandar Bhonde, Nilesh Dagia, Sivaramakrishnan Hariharan, Pramod Bhaskar Kumar, Sanjay Kumar, Pallavi Hanmantrao Mane, Rajiv Sharma. Invention is credited to Mandar Bhonde, Nilesh Dagia, Sivaramakrishnan Hariharan, Pramod Bhaskar Kumar, Sanjay Kumar, Pallavi Hanmantrao Mane, Rajiv Sharma.
United States Patent |
8,741,932 |
Kumar , et al. |
June 3, 2014 |
Imidazopyridine derivatives
Abstract
The present invention relates to compounds of formula (I),
##STR00001## wherein R.sub.a, R.sub.b, R.sub.c, R.sub.d, R.sub.e
and R.sub.f are as defined in the specification, processes for
their preparation, pharmaceutical compositions containing them and
their use in the treatment of diseases mediated by
phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin
(mTOR), Signal transducer and activator of transcription 3 (STAT
3), tumor necrosis factor-.alpha. (TNF-.alpha.), interleukin-6
(IL-6) or a combination thereof particularly in the treatment of
cancer and inflammation.
Inventors: |
Kumar; Sanjay (Mumbai,
IN), Hariharan; Sivaramakrishnan (Mumbai,
IN), Bhonde; Mandar (Pune, IN), Dagia;
Nilesh (Mumbai, IN), Sharma; Rajiv (Mumbai,
IN), Mane; Pallavi Hanmantrao (Mumbai, IN),
Kumar; Pramod Bhaskar (Mumbai, IN) |
Applicant: |
Name |
City |
State |
Country |
Type |
Kumar; Sanjay
Hariharan; Sivaramakrishnan
Bhonde; Mandar
Dagia; Nilesh
Sharma; Rajiv
Mane; Pallavi Hanmantrao
Kumar; Pramod Bhaskar |
Mumbai
Mumbai
Pune
Mumbai
Mumbai
Mumbai
Mumbai |
N/A
N/A
N/A
N/A
N/A
N/A
N/A |
IN
IN
IN
IN
IN
IN
IN |
|
|
Assignee: |
Piramal Enterprises Limited
(Mumbai, IN)
|
Family
ID: |
43448356 |
Appl.
No.: |
13/508,135 |
Filed: |
November 4, 2010 |
PCT
Filed: |
November 04, 2010 |
PCT No.: |
PCT/IB2010/054996 |
371(c)(1),(2),(4) Date: |
May 04, 2012 |
PCT
Pub. No.: |
WO2011/055320 |
PCT
Pub. Date: |
May 12, 2011 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20120232072 A1 |
Sep 13, 2012 |
|
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
61258685 |
Nov 6, 2009 |
|
|
|
|
Current U.S.
Class: |
514/333; 544/127;
544/105; 514/233.2; 514/230.5; 546/121; 514/256 |
Current CPC
Class: |
A61P
37/02 (20180101); A61P 35/00 (20180101); A61P
25/00 (20180101); A61P 11/06 (20180101); A61P
21/00 (20180101); A61P 7/00 (20180101); A61P
11/00 (20180101); A61P 17/14 (20180101); A61P
35/02 (20180101); A61P 17/04 (20180101); A61P
37/08 (20180101); A61P 19/02 (20180101); A61P
31/18 (20180101); A61P 33/06 (20180101); A61P
19/04 (20180101); A61P 37/06 (20180101); A61P
1/16 (20180101); A61P 31/14 (20180101); A61P
9/00 (20180101); A61P 19/10 (20180101); A61P
27/02 (20180101); A61P 19/08 (20180101); C07D
471/04 (20130101); A61P 17/06 (20180101); A61P
37/00 (20180101); A61P 1/00 (20180101); A61P
25/28 (20180101); A61P 29/00 (20180101); A61P
15/00 (20180101); A61P 31/04 (20180101); A61P
3/10 (20180101); A61P 43/00 (20180101); A61P
1/04 (20180101); A61P 17/00 (20180101); A61P
9/10 (20180101) |
Current International
Class: |
A01N
43/40 (20060101); C07D 498/02 (20060101); C07D
413/00 (20060101); C07D 265/36 (20060101); C07D
491/02 (20060101); A61K 31/535 (20060101); A01N
43/54 (20060101); A61K 31/44 (20060101) |
Field of
Search: |
;546/121
;514/300,233.2,256,230.5 ;544/127,105,333 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Jose et al., The Oncologist (2011), 16 (suppl 1): 12-19. cited by
examiner .
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1048-1051. cited by examiner .
Wullschleger , Stephan, et al., "TOR Signaling in Growth and
Metabolism", Cell 124, Feb. 10, 2006, pp. 471-484. cited by
applicant .
Hennessy, Bryan T., et al., "Exploiting the P13K/AKT Pathway for
Cancer Drug Discovery", Nature Reviews Drug Discovery, Dec. 2005,
vol. 4, pp. 988-1004. cited by applicant .
Maier, Gerhard, et al., "Absence of tumor growth stimulation in a
panel of 16 human tumor cell lines by mistletoe extracts in vitro",
Anti-Cancer Drugs, 2002, vol. 13, pp. 1-7. cited by applicant .
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Peripheral Blood Mononuclear Cells Stimulated by LPS or Infected by
Borrelia", Physiol. Res. 52, 2003, pp. 593-598. cited by applicant
.
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in a murine model of colitis", Am J Physiol Gastrointest Liver
Physiol 295, Oct. 15, 2008, pp. G1237-G1245. cited by applicant
.
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Antibodies on Synovial Cell Interleukin-1 Production in Rheumatoid
Arthritis" The Lancet, Jul. 29, 1989, pp. 244-247. cited by
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for p42/p44 mitogen-activated protein kinase (MAPK), p38 MAPK,
protein kinase B and cAMP-response-element-binding protein",
Biochem J 350, 2000, pp. 717-722. cited by applicant .
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Family Defines a Role for p110.alpha. in Insulin Signaling", Cell
125, May 19, 2006, pp. 733-747. cited by applicant .
Liu, Pixu, et al. Targeting the phosphoinositide 3-kinase pathway
in cancer. Nature Reviews/Drug Discovery, vol. 8, pp. 627-644. Aug.
2009. cited by applicant .
Bradley, J.R. TNF-mediated inflammatory disease. Journal of
Pathology vol. 214. pp. 149-160. Aug. 2008. cited by applicant
.
Grunke, M., et al. Successful treatment of inflammatory knee
osteoarthritis with tumour necrosis factor blockade. Ann Rheum Dis.
vol. 65, p. 555. 2006. cited by applicant .
McMachon, Mark S., et al. Does Anti-TNF-Alpha Have a Role in the
Treatment of Osteoporosis? Bulletin of the NYU Hospital for Joint
Diseases. vol. 66(4), pp. 280-281. 2008. cited by applicant .
Abstract of: Sands, Bruce E., al. The Role of TNFa in Ulcerative
Colitis. Journal of Clinical Pharmacology, vol. 74, Issue 8, pp.
930-941. Aug. 2007. cited by applicant .
Chang, F. et al., Involvement of P13K/Akt pathway in cell cycle
progression, apoptosis, and neoplastic transformation: a target for
cancer chemotherapy. Leukemia 2003, 17, 590-603. cited by applicant
.
Yuan, TL, et al., P13K pathway alterations in cancer/variations on
a theme. Oncogene, 2008, 27(41), 5497-5510. cited by applicant
.
Raynaud, Florence I. et al, Biological properties of potent
inhibitors of class I phosphatidylinositide 3-kinases; from PI-103
through PI-540k, PI 620 to the oral agent GCD-0941, Molecular
Cancer Therapeutics, 2009 8(7), 1725-1738. cited by applicant .
Serra, Violeta, et al, NVP-BEZ235, a Dual PI3K/mTOR Inhibitor,
Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells
with Activating P13K Mutations. Cancer Research, 2008,68 (19),
8022-8030. cited by applicant .
Brachmann, Saskia M., et al, Specific apoptosis induction by the
dual PI3K/mTor inhibitor NVP-BEZ235 in HER 2 amplified and PIK3CA
mutant breast cells. Proceedings of the National Academy of
Sciences, 2009, 106 (52), 22299-22304. cited by applicant .
Cao. P. et al, Activity of a novel, dual PI3-kinase/mTor inhibitor
NVP-BEZ235 against primary human pancreatic cancers grown as
orthotopic xenografts. British Journal of Cancer. 2009, 100,
1267-1276. cited by applicant.
|
Primary Examiner: Rahmani; Niloofar
Attorney, Agent or Firm: Ladas & Parry LLP
Parent Case Text
This is a 371 application of PCT/IN2010/054996 filed on 4 Nov.
2010, entitled "IMIDAZOPYRIDINE DERIVATIVES", which was published
in the English language on 12 May 2011, with International
Publication Number WO 2011/055320A1, and which claims priority from
U.S. patent application 61/258,68 5filed 6 Nov. 2009, the content
of which is incorporated herein by reference.
Claims
We claim:
1. A compound of formula (I) ##STR00009## wherein, R.sub.a, R.sub.b
and R.sub.d are independently selected from hydrogen, hydroxy,
halogen, cyano, nitro, --COR.sub.1, --COOR.sub.1, --CONH.sub.2,
--NR.sub.1R.sub.2, --C.sub.1-C.sub.8 alkyl, halo-C.sub.1-C.sub.8
alkyl and --C.sub.1-C.sub.8 alkoxy; R.sub.c is halogen or
heteroaryl; R.sub.e is hydrogen, --C.sub.1-C.sub.8 alkyl,
--C.sub.6-C.sub.14 aryl or heteroaryl; Q is --SO.sub.2,
--C(O)NR.sub.1 or --C(S)NR.sub.1; R.sub.f is --C.sub.1-C.sub.8
alkyl, --(CR.sub.1R.sub.2).sub.p--C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--(CR.sub.1R.sub.2).sub.p heterocyclyl,
--(CR.sub.1R.sub.2).sub.pheteroaryl, --C.sub.3-C.sub.8cycloalkyl,
--C.sub.6-C.sub.14aryl, heteroaryl or heterocyclyl; R.sub.1 and
R.sub.2 are independently selected from hydrogen and lower alkyl; p
is independently an integer from 1 to 3; with the proviso that when
Q is --SO.sub.2, then R.sub.c is not halogen; wherein each of the
above alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl and
heterocyclyl are unsubstituted or substituted with one or more of
the same or different groups selected from halogen, hydroxy,
carbonyl, carboxy, ester, ether, acyl, acyloxy, cyano, amino,
amide, imino, alkylthio, thioester, sulfonyl, nitro,
--C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl,
halo-C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.6 alkoxy, haloalkoxy,
--C.sub.3-C.sub.8 cycloalkyl, --(CR.sub.1R.sub.2).sub.p-aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl; or a stereoisomer, tautomer, N-oxide
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R.sub.a , R.sub.b and
R.sub.d are independently selected from hydrogen and
--C.sub.1-C.sub.8 alkyl; R.sub.c is halogen or heteroaryl; R.sub.e
is hydrogen or --C.sub.1-C.sub.8 alkyl; Q is --SO.sub.2,
--C(O)NR.sub.1 or --C(S)NR.sub.1; R.sub.f is --C.sub.1-C.sub.8
alkyl, --(CR.sub.1R.sub.2).sub.p--C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--(CR.sub.1R.sub.2).sub.p-heterocyclyl,
--(CR.sub.1R.sub.2).sub.p-heteroaryl, --C.sub.3-C.sub.8 cycloalkyl,
--C.sub.6-C.sub.14 aryl, heteroaryl or heterocyclyl; R.sub.1 and
R.sub.2 are independently selected from hydrogen and lower alkyl; p
is independently an integer from 1 to 3; with the proviso that when
Q is --SO.sub.2, then R.sub.1 is not halogen; wherein each of the
above alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl are
unsubstituted or substituted with one or more of the same or
different groups selected from halogen, hydroxy, carbonyl, carboxy,
ester, ether, acyl, acyloxy, cyano, amino,amide, imino, alkylthio,
thioester, sulfonyl, nitro, --C.sub.1-C.sub.6 alkyl,
halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.6 alkoxy, --C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.10 aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl; or a stereoisomer, tautomer, N-oxide
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1, wherein R.sub.a, R.sub.b and
R.sub.d are independently selected from hydrogen and
--C.sub.1-C.sub.4 alkyl; R.sub.c is halogen or heteroaryl; R.sub.e
is hydrogen or --C.sub.1-C.sub.4 alkyl; Q is --SO.sub.2, --C(O)NH
or --C(S)NH; R.sub.f is --C.sub.1-C.sub.8 alkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14aryl,
--(CR.sub.1R.sub.2).sub.p heterocyclyl, --C.sub.3-C.sub.8
cycloalkyl, --C.sub.6-C.sub.14 aryl, heterocyclyl, or heteroaryl;
R.sub.1 and R.sub.2 are independently selected from hydrogen and
lower alkyl; p is independently an integer from 1 to 3; with the
proviso that when Q is --SO.sub.2, then R.sub.c is not halogen;
wherein each of the above alkyl, cycloalkyl, aryl, heteroaryl and
heterocyclyl are optionally and independently substituted with one
or more of the same or different groups selected from halogen,
hydroxy, carbonyl, carboxy, ester, ether, acyl, acyloxy, cyano,
amino, amide, imino, alkylthio, thioester, sulfonyl, nitro,
--C.sub.1-C.sub.6 alkyl, halo--C.sub.1-C.sub.6 alkyl,
halo-C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.6 alkoxy, --NHCOMe,
--S(O).sub.2Me, aryloxy, heterocyclyl and heteroaryl; or a
stereoisomer, tautomer, N-oxide or a pharmaceutically acceptable
salt thereof.
4. The compound according to claim 1, wherein, R.sub.a, R.sub.b and
R.sub.d are independently selected from hydrogen and
--C.sub.1-C.sub.4 alkyl; R.sub.c is halogen or heteroaryl; R.sub.e
is hydrogen or --C.sub.1-C.sub.4 alkyl; Q is --C(O)NH or --C(S)NH;
R.sub.f is --C.sub.1-C.sub.8 alkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--(CR.sub.1R.sub.2).sub.p-heterocyclyl, --C.sub.3-C.sub.8
cycloalkyl, --C.sub.6-C.sub.14 aryl or heteroaryl; R.sub.1 and
R.sub.2 are independently selected from hydrogen and lower alkyl; p
is independently an integer from 1 to 3; wherein each of the above
alkyl, cycloalkyl, aryl and heteroaryl are optionally and
independently substituted with one or more of the same or different
groups selected from halogen, hydroxy, cyano, amino, nitro, alkoxy,
--C.sub.1-C.sub.6 alkyl and halo --C.sub.1-C.sub.6 alkyl; or a
stereoisomer, tautomer, N-oxide or a pharmaceutically acceptable
salt thereof.
5. The compound according to claim 1, wherein R.sub.a, R.sub.b and
R.sub.d are independently selected from hydrogen and
--C.sub.1-C.sub.4 alkyl; R.sub.c is halogen or heteroaryl; R.sub.e
is hydrogen or --C.sub.1-C.sub.4 alkyl; Q is --C(O)NH or --C(S)NH;
R.sub.f is --(CR.sub.1R.sub.2).sub.p-heterocyclyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl or
--C.sub.6-C.sub.14 aryl; R.sub.1 and R.sub.2 are independently
selected from hydrogen and lower alkyl; p is independently an
integer from 1 to 3; wherein each of the above alkyl, aryl and
heteroaryl are optionally and independently substituted with one or
more of the same or different groups selected from halogen,
hydroxy, cyano, amino, nitro, alkoxy, --C.sub.1-C.sub.6 alkyl and
halo --C.sub.1-C.sub.6 alkyl; or a stereoisomer, tautomer, N-oxide
or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1, wherein R.sub.a, R.sub.b and
R.sub.d are independently selected from hydrogen and
--C.sub.1-C.sub.4 alkyl; R.sub.c is halogen; R.sub.e is hydrogen or
--C.sub.1-C.sub.4 alkyl; Q is --C(O)NH or --C(S)NH; R.sub.f is
--(CR.sub.1R.sub.2).sub.p-heterocyclyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl or
--C.sub.6-C.sub.14 aryl; R.sub.1 and R.sub.2 are independently
selected from hydrogen and lower alkyl; p is independently an
integer from 1 to 3; wherein each of the above alkyl, aryl and
heteroaryl are optionally and independently substituted with one or
more of the same or different groups selected from halogen,
hydroxy, cyano, amino, nitro, alkoxy, --C.sub.1-C.sub.6 alkyl and
halo-C.sub.1-C.sub.6 alkyl; or a stereoisomer, tautomer, N-oxide or
a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1, wherein R.sub.a, R.sub.b and
R.sub.d are independently selected from hydrogen and
--C.sub.1-C.sub.4 alkyl; R.sub.c is heteroaryl; R.sub.e is hydrogen
or --C.sub.1-C.sub.4 alkyl; Q is --SO.sub.2, --C(O)NR.sub.1 or
--C(S)NR.sub.1; R.sub.f is --C.sub.1-C.sub.8 alkyl,
--(CR.sub.1R.sub.2).sub.1--C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--(CR.sub.1R.sub.2).sub.p-heterocyclyl,
--(CR.sub.1R.sub.2).sub.p-heteroaryl, --C.sub.3-C.sub.8 cycloalkyl,
--C.sub.6-C.sub.14 aryl, heteroaryl or heterocyclyl; R.sub.1 and
R.sub.2 are independently selected from hydrogen and lower alkyl; p
is independently an integer from 1 to 3; wherein each of the above
alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally
and independently substituted with one or more of the same or
different groups selected from halogen, hydroxy, carbonyl, carboxy,
ester, ether, acyl, acyloxy, cyano, amino, amide, imino, alkylthio,
thioester, sulfonyl, nitro, --C.sub.1-C.sub.6 alkyl,
halo--C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.10 aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl; or a stereoisomer, tautomer, N-oxide
or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1, wherein R.sub.a, R.sub.b and
R.sub.d are independently selected from hydrogen and
--C.sub.1-C.sub.4 alkyl; R.sub.c is heteroaryl; R.sub.e is hydrogen
or --C.sub.1-C.sub.4 alkyl; Q is --SO.sub.2, --C(O)NH or --C(S)NH;
R.sub.f is --C.sub.1-C.sub.8 alkyl,
--(CH.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--(CH.sub.2).sub.p-heterocyclyl, --C.sub.3-C.sub.8 cycloalkyl,
--C.sub.6-C.sub.14 aryl, heteroaryl or heterocyclyl; p is
independently an integer from 1 to 3; R.sub.1 and R.sub.2 are
independently selected from hydrogen and lower alkyl; wherein each
of the above alkyl, aryl, heterocyclyl and heteroaryl are
optionally and independently substituted with one or more of the
same or different groups selected from halogen, hydroxy, carbonyl,
carboxy, ester, ether, acyl, acyloxy, cyano, amino, amide, imino,
alkylthio, thioester, sulfonyl, nitro, --C.sub.1-C.sub.6 alkyl,
halo--C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.10 aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl; or a stereoisomer, tautomer, N-oxide
or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1, wherein R.sub.a, R.sub.b and
R.sub.d are independently selected from hydrogen and methyl;
R.sub.c is halogen or heteroaryl selected from indolyl, pyrrolyl,
pyridyl, pyrimidinyl and quinolinyl wherein each of indolyl,
pyrrolyl, pyridyl, pyrimidinyl and quinolinyl is optionally
substituted with one or more groups selected from halogen,
--C.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-alkoxy, and
halo--C.sub.1-C.sub.6-alkyl; R.sub.e is hydrogen or
--C.sub.1-C.sub.4 alkyl; Q is --SO.sub.2, --C(O)NH or --C(S)NH;
R.sub.f is --C.sub.1-C.sub.8 alkyl,
--(CH.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--(CH.sub.2).sub.p-heterocyclyl, --C.sub.3-C.sub.8-cycloalkyl,
--C.sub.6-C.sub.14 aryl, heterocyclyl or heteroaryl; p is
independently an integer from 1 to 3; R.sub.1 and R.sub.2 are
independently selected from hydrogen and lower alkyl; with the
proviso that when Q is --SO.sub.2, then R.sub.c is not halogen;
wherein each of the above alkyl, cycloalkyl, aryl, heteroaryl and
heterocyclyl are optionally and independently substituted with one
or more of the same or different groups selected from halogen,
hydroxy, carbonyl, carboxy, ester, ether, acyl, acyloxy, cyano,
amino, amide, imino, alkylthio, thioester, sulfonyl, nitro,
--C.sub.1-C.sub.6 alkyl, halo--C.sub.1-C.sub.6 alkyl,
halo--C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.6 alkoxy,
--C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.10 aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl group; a stereoisomer, tautomer,
N-oxide or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1, wherein R.sub.a, R.sub.b and
R.sub.d are independently selected from hydrogen and
--C.sub.1-C.sub.4 alkyl; R.sub.c is heteroaryl; R.sub.e is hydrogen
or --C.sub.1-C.sub.4alkyl; Q is --SO.sub.2; R.sub.f is
--C.sub.1-C.sub.8 alkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl, --C.sub.3-C.sub.8
cycloalkyl, --C.sub.6-C.sub.14 aryl, heterocyclyl or heteroaryl;
R.sub.1 and R.sub.2 are independently selected from hydrogen and
lower alkyl; p is independently an integer from 1 to 3; wherein
each of the above alkyl, cycloalkyl, aryl, heterocyclyl and
heteroaryl are unsubstituted or substituted with one or more of the
same or different groups selected from halogen, hydroxy, carbonyl,
carboxy, ester, ether, acyl, acyloxy, cyano, amino, amide, imino,
alkylthio, thioester, sulfonyl, nitro, --C.sub.1-C.sub.6 alkyl,
halo--C.sub.1-C.sub.6 alkyl, halo--C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.6 alkoxy, --C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R-.sub.2).sub.p--C.sub.6-C.sub.10aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl group; or a stereoisomer, tautomer,
N-oxide or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1, wherein R.sub.a, R.sub.b and
R.sub.d are independently selected from hydrogen and methyl;
R.sub.c is heteroaryl selected from indolyl, pyrrolyl, pyridyl,
pyrimidinyl and quinolinyl, wherein each of indolyl, pyrrolyl,
pyridyl, pyrimidinyl and quinolinyl is optionally substituted with
one or more groups selected from halogen, --C.sub.1-C.sub.6-alkyl,
--C.sub.1-C.sub.6-alkoxy, and halo--C.sub.1-C.sub.6-alkyl; R.sub.e
is hydrogen or --C.sub.1-C.sub.4 alkyl; Q is --SO.sub.2; R.sub.f is
--(CH.sub.2).sub.p--C.sub.6-C.sub.14 aryl, --C.sub.3-C.sub.8
cycloalkyl, --C.sub.6-C.sub.14 aryl, heteroaryl or heterocyclyl;
R.sub.1 and R.sub.2 are independently selected from hydrogen and
lower alkyl; p is independently an integer from 1 to 3; wherein
each of the above alkyl, cycloalkyl, aryl, heterocyclyl and
heteroaryl are unsubstituted or substituted with one or more of the
same or different groups selected from halogen, hydroxy, carbonyl,
carboxy, ester, ether, acyl, acyloxy, cyano, amino, amide, imino,
alkylthio, thioester, sulfonyl, nitro, --C.sub.1-C.sub.6 alkyl,
halo--C.sub.1-C.sub.6 alkyl, halo--C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.6 alkoxy, --C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.10 aryl,
--C.sub.6-C.sub.10aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl group; or a stereoisomer, tautomer,
N-oxide or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1, selected from:
N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)benzen-
esulfonohydrazide;
N,3-dimethyl-N'-((6-pyridin-3-yl)imidazo[1,2-a]pyridine-3-yl)methylene)
benzenesulfonohydrazide;
N,4-dimethyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)methylene)
benzenesulfonohydrazide;
2-Fluoro-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)methy-
lene) benzenesulfonohydrazide;
3-Fluoro-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)
methylene)benzenesulfonohydrazide;
4-Fluoro-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)methy-
lene) benzenesulfonohydrazide;
3-Bromo-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)methyl-
ene) benzenesulfonohydrazide;
4-Bromo-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)methyl-
ene) benzenesulfonohydrazide;
2-Cyano-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)methyl-
ene) benzenesulfonohydrazide;
(E)-3-cyano-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)benzenesulfonohydrazide;
4-Cyano-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)methyl-
ene) benzenesulfonohydrazide;
4-Methoxy-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)
methylene)benzenesulfonohydrazide;
2,4-Difluoro-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)m-
ethylene) benzenesulfonohydrazide;
2,6-Difluoro-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)m-
ethylene) benzenesulfonohydrazide;
3,4-difluoro-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)m-
ethylene) benzenesulfonohydrazide;
3,5-Difluoro-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)m-
ethylene) benzenesulfonohydrazide;
3-Chloro-2-fluoro-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-
-yl) methylene)benzenesulfonohydrazide;
3-Chloro-4-fluoro-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-
-yl) methylene)benzenesulfonohydrazide;
2-Fluoro-N,5-dimethyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)m-
ethylene) benzenesulfonohydrazide;
3-Fluoro-N,4-dimethyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)m-
ethylene) benzenesulfonohydrazide;
5-Fluoro-N,2-dimethyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)m-
ethylene) benzenesulfonohydrazide;
3-(3-((2-(5-fluoro-2-methylphenylsulfonyl)-2-methylhydrazono)methyl)imida-
zo[1,2-a]pyridin-6-yl)pyridine 1-oxide;
4-Bromo-N,3-dimethyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)
methylene)benzenesulfonohydrazide;
N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)methylene)-3,5-
-bis (trifluoromethyl)benzenesulfonohydrazide;
3-Cyano-4-fluoro-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3--
yl) methylene)benzenesulfonohydrazide;
N,2-dimethyl-5nitro-N'-((6-pyridin-3-yl)imidazo[1,2-a]pyridine-3-yl)
methylene)benzenesulfonohydrazide;
2-Bromo-4,6-difluoro-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridin-
e-3-yl) methylene)benzenesulfonohydrazide;
N,2,4,6-tetramethyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)met-
hylene) benzenesulfonohydrazide;
N-methyl-1-phenyl-N'-((6-pyridin-3-yl)imidazo[1,2-a]pyridine-3-yl)methyle-
ne) benzenesulfonohydrazide;
N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)methylene)thio-
phene-2-sulfonohydrazide;
N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)methylene)
quinoline-8-sulfonohydrazide;
N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)methylene)
cyclohexanesulfonohydrazide;
3-Fluoro-N,4-dimethyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)m-
ethylene) benzenesulfonohydrazide;
3-Cyano-4-fluoro-N-methyl-N'-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-3--
yl) methylene)benzenesulfonohydrazide;
(E)-2,3,4-Trifluoro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-
-yl) methylene)benzenesulfonohydrazide;
(E)-4-bromo-2,5-difluoro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyri-
din-3-yl) methylene)benzenesulfonohydrazide;
(E)-2-bromo-4-fluoro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl) methylene)benzenesulfonohydrazide;
(E)-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-3-
-(trifluoromethyl) benzenesulfonohydrazide;
(E)-4-bromo-2,6-dichloro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyri-
din-3-yl) methylene)benzenesulfonohydrazide;
(E)-3-chloro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)
methylene)benzenesulfonohydrazide;
(E)-2-chloro-N-methyl-N'-((6-(pyridin-3yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)-4-(trifluoromethyl)benzenesulfonohydrazide;
(E)-2-chloro-4-fluoro-N-methyl-N'((6-(pyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl) methylene)benzenesulfonoydrazide;
(E)-N,1,2-trimethyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methy-
lene)-1H-imidazole-4-sulfonohydrazide;
(E)-4-chloro-N,2,5-trimethyl-N'((6-(pyridin-3-yl)imidazo
[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
(E)-2,5-difluoro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl-
)methylene) benzenesulfonohydrazide;
(E)-5-fluoro-2-methoxy-N-methyl-N'((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-
-3-yl) methylene)benzenesulfonohydrazide;
(E)-4-Iodo-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)
methylene)benzenesulfonohydrazide;
(E)-2'-Fluoro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)me-
thylene)-5'-(trifluoromethyl)biphenyl-4-sulfonohydrazide;
4-Methyl-3-(1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methy-
lene) hydrazinylsulfonyl)benzoic acid;
4-Methoxy-3-(1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)
methylene)hydrazinylsulfonyl)benzamide;
(E)-N,2,5-trimethyl-N'((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methyl-
ene) benzenesulfonohydrazide;
(E)-2,5-dibromo-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)-
methylene) benzenesulfonohydrazide;
(E)-2,5-dimethoxy-N-methyl-N'((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl-
)methylene) benzenesulfonohydrazide;
(E)-N,2-dimethyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylen-
e) benzenesulfonohydrazide;
(E)-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-2-
-(trifluoromethoxy )benzenesulfonohydrazide;
(E)-5-chloro-2-methoxy-N-methyl-N-'-((6-(pyridin-3-yl)imidazo[1,2-a]pyrid-
in-3-yl) methylene)benzenesulfonohydrazide;
(E)-4-bromo-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)-2-(trifluoromethoxy)benzenesulfonohydrazide;
(E)-2-bromo-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)-5-(trifluoromethyl)benzenesulfonohydrazide;
(E)-N-methyl-2-nitro-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)
methylene)benzenesulfonohydrazide;
(E)-N-methyl-2-(methylsulfonyl)-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridi-
n-3-yl) methylene)benzenesulfonohydrazide
(E)-N-methyl-2-phenoxy-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)
methylene)benzenesulfonohydrazide;
(E)-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)
hexane-1-sulfonohydrazide;
(E)-N-methyl-2-morpholino-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl-
)methylene)-5-(trifluoromethyl)benzenesulfonohydrazide;
(E)-N,2-dimethyl-5-(methylsulfonyl)-N'-((6-(pyridin-3-yl)imidazo[1,2-a]py-
ridin-3-yl) methylene)benzenesulfonohydrazide;
(E)-2-bromo-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene) benzenesulfonohydrazide;
(E)-2-chloro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)met-
hylene)-5-(trifluoromethyl)benzenesulfonohydrazide;
(E)-N-methyl-6-morpholino-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl-
)methylene) pyridine-3-sulfonohydrazide
(E)-Methyl1-methyl-5-(1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl) methylene)hydrazinylsulfonyl)-1H-pyrrole-2-carboxylate;
(E)-N,4-dimethyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylen-
e)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-sulfonohydrazide;
(E)-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)py-
ridine-3-sulfonohydrazide;
(E)-N-methyl-4-phenoxy-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)me-
thylene) benzenesulfonohydrazide;
(E)-Methyl3-(1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene) hydrazinylsulfonyl)thiophene-2-carboxylate;
(E)-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)bi-
phenyl-4-sulfonohydrazide;
(E)-Methyl5-(1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)hydrazinylsulfonyl) furan-2-carboxylate;
(E)-4-chloro-N-methyl-3-nitro-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl)methylene) benzenesulfonohydrazide;
(E)-5-bromo-2-methoxy-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-
-3-yl) methylene)benzenesulfonohydrazide;
(E)-3-chloro-N,2-dimethyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl-
)methylene) benzenesulfonohydrazide;
(E)-5-chloro-2-fluoro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-
-3-yl) methylene)benzenesulfonohydrazide;
(E)-4-Fluoro-N,2-dimethyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl-
)methylene) benzenesulfonohydrazide;
(E)-2-methoxy-N,6-dimethyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-y-
l) methylene)benzenesulfonohydrazide;
(E)-4-Bromo-2-chloro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl) methylene)benzenesulfonohydrazide;
(E)-2-chloro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)met-
hylene) benzenesulfonohydrazide;
(E)-N-(4-(1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methyle-
ne) hydrazinylsulfonyl)phenyl)acetamide;
N'-((6-(6-fluoropyridine-3-yl)imidazo[1,2-a]pyridine-3-yl)methylene)-n,2--
dimethyl-5-nitrobenzenesulfonohydrazide;
(E)-N-ethyl-2-methyl-5-nitro-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-
-yl) methylene)benzenesulfonohydrazide;
N,2-dimethyl-5-nitro-N'-((6-(pyridine-4-yl)imidazo[1,2-a]pyridine-3-yl)me-
thylene) benzenesulfonohydrazide;
5-Fluoro-N,2-dimethyl-N'-((6-(pyridine-4-yl)imidazo[1,2-a]pyridine-3-yl)m-
ethylene) benzenesulfonohydrazide;
(E)-5-Fluoro-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)-N,2-dimethylbenzenesulfonohydrazide;
(E)-5-Fluoro-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)-2-methoxy-N-methylbenzenesulfonohydrazide;
(E)-3-fluoro-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)-N-methylbenzenesulfonohydrazide;
(E)-5-chloro-2-fluoro-N'46-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3--
yl)methylene)-N-methylbenzenesulfonohydrazide;
(E)-5-bromo-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methy-
lene)-2-methoxy-N-methylbenzenesulfonohydrazide
(E)-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-2,-
5-dimethoxy-N-methylbenzenesulfonohydrazide;
(E)-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-N,-
2-dimethyl-5-(methylsulfonyl)benzenesulfonohydrazide;
(E)-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-N--
methylhexane-1-sulfonohydrazide;
(E)-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-2--
methoxy-N,4-dimethylbenzenesulfonohydrazide;
(E)-2-bromo-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methy-
lene)-N-methylbenzenesulfonohydrazide;
(E)-2-cyano-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methy-
lene)-N-methylbenzenesulfonohydrazide;
(E)-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-2--
methoxy-N,5-dimethylbenzenesulfonohydrazide;
N,2-Dimethyl-5-nitro-N'-((6-(quinolin-3-yl)imidazo[1,2-a]pyridine-3-yl)me-
thylene) benzenesulfonohydrazide;
(E)-5-Fluoro-N,2-dimethyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyr-
idin-3-yl)methylene)benzenesulfonohydrazide;
(E)-3,5-Difluoro-N-methyl-N'-((8-methyl-6-(pyridin-3-ypimidazo[1,2-a]pyri-
din-3-yl)methylene)benzenesulfonohydrazide;
(E)-4-Bromo-2,6-difluoro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1-
,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide;
(E)-N,3-dimethyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl-
)methylene)benzenesulfonohydrazide;
(E)-2-cyano-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl)methylene)benzenesulfonohydrazide;
(E)-3-cyano-4-fluoro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a-
]pyridin-3-yl)methylene)benzenesulfonohydrazide;
(E)-3-cyano-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl)methylene)benzenesulfonohydrazide;
(E)-4-Bromo-N,3-dimethyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyri-
din-3-yl)methylene)benzenesulfonohydrazide;
(E)-3-Methoxy-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridi-
n-3-yl)methylene)benzenesulfonohydrazide;
(E)-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)met-
hylene)-3-nitrobenzenesulfonohydrazide;
(E)-3-Chloro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-
-3-yl)methylene)benzenesulfonohydrazide;
(E)-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)met-
hylene)-3-(trifluoromethyl)benzenesulfonohydrazide;
(E)-2-Bromo-4,6-difluoro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1-
,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide;
(E)-4-Chloro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-
-3-yl)methylene)-3-nitrobenzenesulfonohydrazide;
(E)-2-Bromo-4-fluoro-N-methyl-N'((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]-
pyridin-3-yl)methylene)benzenesulfonohydrazide;
(E)-N'-((6-(1H-indol-2-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-5-fluoro--
N,2-dimethylbenzenesulfonohydrazide;
(E)-5-fluoro-N,2-dimethyl-N'-((6-(1-methyl-1H-indol-3-yl)imidazo[1,2-a]py-
ridin-3-yl)methylene benzenesulfonohydrazide;
2-Cyano-N-methyl-N'((7-methyl-6-(pyridin-3-yl)imidazo
[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
5-Fluoro-N,2-dimethyl-N'-((7-methyl-6-(pyridin-3-yl)imidazo
[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
N,3-dimethyl-N'-((7-methyl-6-(pyridin-3-yl)imidazo
[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
3-Fluoro-N-methyl-N'((7-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl-
)methylene) benzenesulfonohydrazide;
3-Chloro-N-methyl-N'-((7-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-y-
l)methylene )benzenesulfonohydrazide;
N-methyl-N'-((7-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methyle-
ne)-3-(trifluoromethyl)benzenesulfonohydrazide;
3-Bromo-N-methyl-N'((7-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)
methylene)benzenesulfonohydrazide;
5-Fluoro-N,2-dimethyl-N'-((7-methyl-6-(pyridin-3-yl)imidazo
[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
N'-((6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-
-5-fluoro-N,2-dimethylbenzenesulfonohydrazide;
(E)-5-Fluoro-N,2-dimethyl-N'-((5-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyr-
idin-3-yl)methylene)benzenesulfonohydrazide;
(E)-N,3-dimethyl-N'-((5-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl-
)methylene)benzenesulfonohydrazide;
(E)-5-fluoro-N,2-dimethyl-N'-((6-(6-methylpyridin-3-yl)imidazo[1,2-a]pyri-
din-3-yl)methylene)benzenesulfonohydrazide;
(E)-N-methyl-N'-((6-(6-methylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)-2-(trifluoromethoxy)benzenesulfonohydrazide;
(E)-5-Fluoro-2-methoxy-N-methyl-N'-((6-(6-methylpyridin-3-yl)imidazo
[1,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide;
(E)-N,2-dimethyl-N'((6-(6-methylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)m-
ethylene)benzenesulfonohydrazide;
(E)-5-fluoro-N'-((6-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)-N,2-dimethyl benzenesulfonohydrazide;
(E)-5-Fluoro-N'((6-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methy-
lene)-2-methoxy-N-methyl benzenesulfonohydrazide;
(E)-5-Fluoro-N'-((6-(6-fluoro-5-methylpyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl)methylene)-N,2-dimethyl benzenesulfonohydrazide;
(E)-N'-((6-(6-Chloropyridins-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-5-
-fluoro-N,2-dimethylbenzenesulfonohydrazide;
(E)-N'-((6-(1H-Pyrrol-2-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-5-fluoro-
-N,2-dimethyl benzenesulfonohydrazide;
(E)-5-fluoro-N'-((6-(6-methoxypyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)met-
hylene)-N,2-dimethyl benzenesulfonohydrazide;
(E)-5-Fluoro-N-((6-(2-methoxypyrimidin-5-yl)imidazo[1,2-a]pyridine-3-yl)m-
ethylene)-N,2-dimethylbenzenesulfonohydrazide;
(E)-5-fluoro-N,2-dimethyl-N'-((6-(5-(trifluoromethyl)pyridin-3-yl)imidazo
[1,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide;
(E)-5-Fluoro-N,2-dimethyl-N-((6-(pyrimidin-5-ypimidazo[1,2-a]pyridin-3-yl-
)methylene)benzenesulfonohydrazide;
(E)-N-benzyl-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)hydrazinecarboxamide;
(E)-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-N--
p-tolylhydrazinecarboxamide;
(E)-N-(2-fluoro-5-methylphenyl)-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2--
a]pyridin-3-yl)methylene)hydrazinecarboxamide;
(E)-N-(5-fluoro-2-methylphenyl)-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2--
a]pyridin-3-yl)methylene)hydrazinecarboxamide;
N-benzyl-2-((6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-1-methyl
hydrazinecarboxamide;
(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-N-(2-fluoro-5-methylphenyl)-
-1-methylhydrazinecarboxamide;
(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-N-(5-fluoro-2-methlphenyl)--
1-methylhydrazinecarboxamide;
(E)-1-methyl-N-(2-morpholinoethyl)-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyri-
din-3-yl)methylene)hydrazinecarbothioamide;
(E)-N-(4-cyanophenyl)-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl)methylene)hydrazinecarbothioamide;
(E)-N-(4-methoxyphenyl)-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridi-
n-3-yl)methylene)hydrazinecarbothioamide;
2-((6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-1-methyl-N-(2-morpholino-
ethyl)hydrazinecarbothioamide;
2-((6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-1-methyl-N-(4-(trifluoro-
methyl)phenyl)hydrazinecarbothioamide; or a stereoisomer, tautomer,
N-oxide or a pharmaceuticallyacceptable salt thereof.
13. A pharmaceutical composition, comprising a therapeutically
effective amount of a compound of formula (I) according claim 1 or
a pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable excipient or carrier.
14. A method for the treatment of a disease mediated by PI3K
(phosphatidylinositol-3-kinase) or mTOR (mammalian target of
rapamycin) or STAT3(Signal transducer and activator of
transcription 3) or a combination thereof, comprising,
administering to a mammal in need thereof a therapeutically
effective amount of a compound of formula (I) according to claim 1
or a pharmaceutically acceptable salt thereof, wherein the disease
is cancer is selected from the group consisting of small-cell-lung
cancer, non-small-cell lung cancer, prostate cancer, ovarian
cancer, colorectal cancer, pancreatic cancer, breast cancer and
glioblastoma.
15. A method for the treatment of a disease mediated by
TNF-.alpha.or IL-6 , comprising administering to a mammal in need
thereof a therapeutically effective amount of a compound of formula
(I) according to claim 1 or a pharmaceutically acceptable salt
thereof, wherein the disease mediated by TNF-.alpha.or IL-6 is
selected from the group consisting of psoriasis, inflammatory bowel
disease, inflammation, rheumatoid arthritis, juvenile rheumatoid
arthritis, psoriatic arthritis, osteoarthritis, refractory
rheumatoid arthritis, chronic non-rheumatoid arthritis,
osteoporosis/bone resorption, Crohn's disease, atherosclerosis,
ulcerative colitis, and ankylosing spondylitis.
16. The method according to claim 15, wherein the disease mediated
by TNF-.alpha. or IL-6is selected from the group consisting of
rheumatoid arthritis, Crohn's disease, ulcerative colitis,
psoriasis and atherosclerosis.
17. A process for the preparation of a compound of formula (I)
##STR00010## wherein, Q is SO.sub.2; R.sub.a, R.sub.b and R.sub.d
are hydrogen or methyl; R.sub.c, R.sub.e and R.sub.f are as defined
for formula (I) in claim 1, comprising refluxing a compound of
formula (3) ##STR00011## with a compound of formula
H.sub.2N--NH--R.sub.e in presence of an alcoholic solvent followed
by reacting with a compound of formula R.sub.fSO.sub.2X, wherein Q
is SO.sub.2; X is halogen, R.sub.a, R.sub.b and R.sub.d are
independently hydrogen or methyl, R.sub.c, R.sub.e and R.sub.f are
as defined above for formula (I) in presence of pyridine as a base;
optionally converting the resulting compound into a
pharmaceutically acceptable salt.
18. A process for the preparation of a compound of formula (I)
##STR00012## wherein, Q is --C(O)NH or --C(S)NH; R.sub.a, R.sub.b
and R.sub.d are independently hydrogen or methyl, R.sub.c, R.sub.e
and R.sub.f are as defined for formula (I) in claim 1, which
comprises, refluxing a compound of formula (3) ##STR00013## with a
compound of formula H.sub.2N--NH--R.sub.e in presence of an
alcoholic solvent followed by reacting with a compound of formula
O.dbd.C.dbd.N.dbd.R.sub.f or S.dbd.C.dbd.N.dbd.R.sub.f, wherein
R.sub.a, R.sub.b and R.sub.d are hydrogen or methyl, R.sub.c,
R.sub.e and R.sub.f are as defined above for formula (I);
optionally converting the resulting compound into a
pharmaceutically acceptable salt.
Description
FIELD OF THE INVENTION
The present invention relates to imidazo[1,2-a]pyridine
derivatives, processes for their preparation, pharmaceutical
compositions containing them and their use in the treatment of
diseases mediated by phosphatidylinositol-3-kinase (PI3K),
mammalian target of rapamycin (mTOR), Signal transducer and
activator of transcription 3 (STAT 3), tumor necrosis
factor-.alpha. (TNF-.alpha.), interleukin-6 (IL-6) or a combination
thereof. In particular these compounds can be used in the treatment
of cancer and inflammation.
BACKGROUND OF THE INVENTION
Cancer can be defined as an abnormal growth of tissues
characterized by a loss of cellular differentiation.
The phosphatidylinositol-3-kinase (PI3K) pathway plays an important
role in cellular signaling. Phosphatidylinositol-3-kinases or
phosphoinositol-3-kinases (PI3-kinases or PI3 Ks) are a family of
related enzymes that are capable of phosphorylating the 3 position
hydroxyl group of the inositol ring of phosphatidylinositol. The
PI3K family is composed of Class I, II and Class III. The
classification is based on primary structure, regulation and in
vitro lipid substrate specificity. Class III PI3K enzymes
phosphorylate PI alone while, Class II PI3K enzymes phosphorylate
both PI and PI 4-phosphate [PI(4)P].
Class I PI3K enzymes phosphorylate PI, PI(4)P and PI
4,5-biphosphate[PI(4,5)P.sub.2]. Class I PI3Ks are further divided
into two groups, class Ia and class Ib, in terms of their
activation mechanism. Class Ia PI3Ks include PI3K p110.alpha.,
p110.beta. and p110.delta. subtypes and are generally activated in
response to growth factor-stimulation of receptor tyrosine kinases.
The first two p110 isoforms (.alpha. and .beta.) are expressed in
all cells, but p110.delta. is primarily expressed in leukocytes.
Class Ib enzymes consist of p110.gamma. catalytic subunit that
interacts with a p110 regulatory subunit. It is activated in
response to G-protein coupled receptor systems and its expression
appears to be limited to leukocytes and cardiomyocytes. Class Ia
subtypes are considered to be associated with cell proliferation
and carcinogenesis.
mTOR is a class IV PI-3 kinase family member with protein kinase
activity, but lacks any lipid kinase activity. It regulates cell
growth and metabolism in response to environmental cue hence
inhibitors of mTOR may be useful in the treatment of cancer and
metabolic disorders (Cell, 2006, 124, 471-484).
PI3K mediated signaling pathway plays a very important role in
cancer cell survival, cell proliferation, angiogenesis and
metastasis. The PI3K pathway is activated by stimuli such as growth
factors, hormones, cytokines, chemokines and hypoxic stress.
Activation of PI3K results in the recruitment and activation of
protein kinase B (AKT) to the membrane, which gets phosphorylated
at Serine 473 (Ser-473). Thus, phosphorylation of Ser-473 of AKT is
a read-out/detector for the activation of the PI3K-mediated
pathway. A cell-based ELISA technique can be used to study such
activation.
AKT is known to positively regulate cell growth (accumulation of
cell mass) by activating the mTOR serine threonine kinase. mTOR
serves as a molecular sensor that regulates protein synthesis on
the basis of nutrients. mTOR regulates biogenesis by
phosphorylating and activating p70S6 kinase (S6K1), which in turn
enhances translation of mRNAs that have polypyrimidine tracts. The
phosphorylation status of S6K1 is a bonafide read-out of mTOR
function.
Most tumors have an aberrant PI3K pathway (Nat. Rev. Drug Discov.,
2005, 4, 988-1004). Since mTOR lies immediately downstream of PI3K,
these tumors also have hyperactive mTOR function. Thus, most of the
cancer types can be treated using the molecules that target PI3K
and mTOR pathways.
The compounds that are PI3K and/or mTOR and/or STAT3 inhibitors,
find use in the treatment of cancers. Compounds are used to reduce,
inhibit, or diminish the proliferation of tumor cells, and thereby
assist in reducing the size of a tumor.
Signal transducer and activator of transcription 3 also known as
STAT3 is a transcription factor which in humans is encoded by the
STAT3 gene. The protein encoded by this gene is a member of the
STAT protein family. In response to cytokines and growth factors,
STAT family members are phosphorylated by the receptor associated
kinases, and then form homo- or heterodimers that translocate to
the cell nucleus where they act as transcription activators. STAT3
mediates the expression of a variety of genes in response to cell
stimuli, and thus plays a key role in many cellular processes such
as cell growth and apoptosis. Constitutive STAT3 activation is
associated with various human cancers and commonly suggests poor
prognosis. It has anti-apoptotic as well as proliferative
effects.
The compounds that are STAT3 inhibitors, find use in the treatment
of cancers. These compounds are used to reduce, inhibit, or
diminish the proliferation of tumor cells.
SF 1126 (Semaphore, Inc.) is a pan-PI3K inhibitor in phase I
clinical trials. SF1126 is a covalent conjugate of LY294002
containing a peptide-based targeting group.
GDC-0941 (Piramed Ltd. and Genentech, Inc.) is a PI3K inhibitor and
is in phase I clinical trials.
BEZ-235 (Novartis AG), which is currently in phase I/II clinical
trials, inhibits all isoforms of PI3K and also inhibits the kinase
activity of mTOR.
XL-765 (Exelixis Inc.) is also a dual inhibitor of mTOR and PI3K.
The compound is in phase I clinical trials as an oral treatment for
solid tumors.
PIK-75 (Astellas Pharma Inc.) is in preclinical studies. It is a
PI3Kalpha inhibitor and inhibits p110.alpha.>200 fold more than
plif.beta..
Inflammation is the response of a tissue to injury that may be
caused by a biological assault such as invading organisms and
parasites, ischemia, antigen-antibody reactions or other forms of
physical or chemical injury. It is characterized by increased blood
flow to the tissue, causing pyrexia, erythema, induration and
pain.
Several proinflammatory cytokines, especially TNF-.alpha. and
interleukins (IL-1.beta., IL-6, IL-8) play an important role in the
inflammatory process. Both IL-1 and TNF-.alpha. are derived from
mononuclear cells and macrophages and in turn induce the expression
of a variety of genes that contribute to the inflammatory process.
An increase in TNF-.alpha. synthesis/release is a common phenomenon
during the inflammatory process. Inflammation is an inherent part
of various disease states like rheumatoid arthritis, Crohn's
disease, ulcerative colitis, septic shock syndrome, psoriasis,
atherosclerosis, among other clinical conditions.
The first line of treatment for inflammatory disorders involves the
use of non-steroidal anti-inflammatory drugs (NSAIDs) e.g.
ibuprofen, naproxen to alleviate symptoms such as pain. However,
despite the widespread use of NSAIDs, many individuals cannot
tolerate the doses necessary to treat the disorder over a prolonged
period of time as NSAIDs are known to cause gastric erosions.
Moreover, NSAIDs merely treat the symptoms of disorder and not the
cause. When patients fail to respond to NSAIDs, other drugs such as
methotrexate, gold salts, D-penicillamine and corticosteroids are
used. These drugs also have significant toxic effects.
Monoclonal antibody drugs such as Infliximab, Etanercept and
Adalimumab are useful as anti-inflammatory agents, but have
drawbacks such as route of administration (only parenteral), high
cost, allergy induction, activation of latent tuberculosis,
increased risk of cancer and congestive heart disease.
PI3K inhibitors are known in the art. For example, U.S. Pat. No.
6,403,588 describes phosphatidylinositol 3 kinase inhibitors useful
as antitumor agents. Additionally, WO 2004/017950 describes
phosphatidylinositol 3,5-biphosphate inhibitors as anti-viral
agents.
SUMMARY OF THE INVENTION
The present invention provides imidazo[1,2-a]pyridine derivatives
of formula (I):
##STR00002## in all their stereoisomeric and tautomeric forms and
mixtures thereof in all ratios, prodrugs, N-oxides, and their
pharmaceutically acceptable salts and pharmaceutically acceptable
solvates, wherein, R.sub.a, R.sub.b and R.sub.d are independently
selected from hydrogen, hydroxy, halogen, cyano, nitro,
--COR.sub.1, --COOR.sub.1, --CONH.sub.2, --NR.sub.1R.sub.2,
--C.sub.1-C.sub.8 alkyl, halo-C.sub.1-C.sub.8 alkyl and
--C.sub.1-C.sub.8 alkoxy; R.sub.c is halogen or heteroaryl; R.sub.e
is hydrogen, --C.sub.1-C.sub.8 alkyl, --C.sub.6-C.sub.14 aryl or
heteroaryl; Q is --SO.sub.2--, --C(O)NR.sub.1-- or
--C(S)NR.sub.1--; R.sub.f is --C.sub.1-C.sub.8 alkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--(CR.sub.1R.sub.2).sub.p-heterocyclyl,
--(CR.sub.1R.sub.2).sub.p-heteroaryl, --C.sub.3-C.sub.8cycloalkyl,
--C.sub.6-C.sub.14aryl, heteroaryl or heterocyclyl; R.sub.1 and
R.sub.2 are independently selected from hydrogen and lower alkyl; p
is independently an integer from 1 to 3; with the proviso that when
Q is --SO.sub.2--, then R.sub.c is not halogen; wherein each of the
above alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl and
heterocyclyl are unsubstituted or substituted with one or more of
the same or different groups selected from halogen, hydroxy,
carbonyl, carboxy, ester, ether, acyl, acyloxy, cyano, amino,
amide, imino, alkylthio, thioester, sulfonyl, nitro,
--C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl,
halo-C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.6 alkoxy, haloalkoxy,
--C.sub.3-C.sub.8 cycloalkyl, --(CR.sub.1R.sub.2).sub.p-aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl.
The present invention also provides processes for producing
compounds of formula (I).
The present invention further provides a pharmaceutical composition
comprising a therapeutically effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt thereof, or a
pharmaceutically acceptable solvate thereof, in combination with a
pharmaceutically acceptable excipient, carrier or diluent.
The present invention also provides a method of treating diseases
mediated by PI3K and/or mTOR and/or STAT3 in a mammal comprising
administering to a mammal in need of such treatment an effective
amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
The present invention also provides a method of treating diseases
mediated by TNF-.alpha. and/or IL-6 in a mammal comprising
administering to a mammal in need of such treatment an effective
amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
The present invention also provides a method of inhibiting the
tumor cell growth, tumor cell proliferation or tumorigenesis in a
mammal comprising administering to a mammal in need of such
treatment an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
The present invention also provides a method of treating cancer
mediated by PI3K and/or mTOR and/or STAT3 comprising administering
to a mammal in need of such treatment an effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof.
The present invention further provides a method of treating cancer
comprising administering to a mammal in need of such treatment an
effective amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
The present invention also provides a method of treating
inflammatory conditions mediated by TNF-.alpha. and/or
interleukin-6 (IL-6) comprising administering to a mammal in need
of such treatment an effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of treating
inflammatory conditions comprising administering to a mammal in
need of such treatment an effective amount of a compound of formula
(I) or a pharmaceutically acceptable salt thereof.
The present invention further provides the use of a compound of
formula (I) or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament containing either entity for the
treatment of diseases mediated by PI3K and/or mTOR and/or
STAT3.
The present invention further provides the use of a compound of
formula (I) or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament containing either entity for the
treatment of cancer.
The present invention further provides the use of a compound of
formula (I) or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament containing either entity for the
treatment of diseases mediated by TNF-.alpha. and/or IL-6.
The present invention further provides the use of a compound of
formula (I) or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament containing either entity for the
treatment of inflammatory conditions.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph depicting effect of compound of Example 25 on DSS
induced weight loss (%) in C57BL/6J mice. 5-ASA was used as
positive control
FIG. 2 is a graph depicting effect of compound of Example 25 on DSS
induced shortening of colon in C57BL/6J mice. 5-ASA was used as
positive control
FIG. 3 is a graph depicting effect of compound of Example 25 on DSS
induced decrease in haematocrit in C57BL/6J mice. 5-ASA was used as
positive control
FIG. 4 is a graph depicting effect of compound of Example 25 on DSS
induced rectal bleeding in C57BL/6J mice. 5-ASA was used as
positive control
FIG. 5 is a graph depicting effect of compound of Example 25 on DSS
induced colon bleeding in C57BL/6J mice. 5-ASA was used as positive
control
FIG. 6 is a graph depicting effect of compound of Example 25 on DSS
induced disease activity index in C57BL/6J mice. 5-ASA was used as
positive control
DETAILED DESCRIPTION OF THE INVENTION
Listed below are definitions, which apply to the terms as they are
used throughout the specification and the appended claims (unless
they are otherwise limited in specific instances), either
individually or as part of a larger group. It will be understood
that "substitution" or "substituted with" includes the implicit
proviso that such substitution is in accordance with permitted
valence of the substituted atom and the substituent, as well as
represents a stable compound, which does not readily undergo
transformation such as by rearrangement, cyclization, elimination,
etc.
As used herein, the term "alkyl" whether used alone or as part of a
substituent group, refers to a saturated straight or branched chain
hydrocarbon radical containing the indicated number of carbon
atoms. For example, C.sub.1-C.sub.8 alkyl refers to alkyl group
having 1 to 8 (both inclusive) carbon atoms. In case of absence of
any numerical designation, "alkyl" is a straight or branched-chain
containing from 1 to 6 (both inclusive) carbon atoms. Examples of
alkyl include, but are not limited to, methyl, ethyl, n-propyl,
n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl,
sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl and
3-methylbutyl.
As used herein, the term "lower alkyl" whether used alone or as
part of a substituent group, refers to the radical of saturated
aliphatic groups, including straight or branched chain containing
from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.
Unless stated otherwise, the alkyl and lower alkyl groups as stated
above can be unsubstituted or substituted with one or more of the
same or different groups selected from halogen, oxo, carbonyl,
carboxy, cyano, thioester, sulfonyl, nitro, acyl, acyloxy,
cycloalkyl, aryl, heterocyclyl, heteroaryl, --OR.sub.x, --SR.sub.x,
--NR.sub.yR.sub.z, --CONR.sub.yR.sub.z, --NR.sub.yCOR.sub.z,
--NR.sub.yCONR.sub.yR.sub.z, --NR.sub.ySOR.sub.z,
--NR.sub.ySO.sub.2R.sub.z, --S(O).sub.mR.sub.y and
--S(O).sub.nNR.sub.yR.sub.z, wherein R.sub.x is hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein R.sub.y and
R.sub.z are independently selected from hydrogen, hydroxy, alkyl,
alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and
heterocyclyl; m is an integer from 0 to 2 and n is an integer from
0 to 1. Any kind of substituent present in substituted alkyl
residues can be present in any desired position provided that the
substitution does not lead to an unstable molecule.
As used herein, the term "alkenyl" whether used alone or as part of
a substituent group, refers to a straight or branched chain
hydrocarbon radical containing the indicated number of carbon atoms
and at least one carbon-carbon double bond (two adjacent sp.sup.2
carbon atoms). For example, C.sub.2-C.sub.8 alkenyl refers to an
alkenyl group having 1 to 8 (both inclusive) carbon atoms.
Depending on the placement of double bond and substituents if any,
the geometry of the double bond may be entgegen (E), or zusammen
(Z), cis or trans. Examples of alkenyl include, but are not limited
to, vinyl and allyl. Unless stated otherwise, the alkenyl groups
can be unsubstituted or substituted with one or more of the same or
different groups selected from halogen, hydroxy, carboxy, acetoxy,
amino, cyano, nitro, alkyl, alkoxy, cycloalkyl, aryloxy, aryl,
aralkyl and heterocyclyl.
As used herein, the term "alkynyl" whether used alone or as part of
a substituent group, refers to a straight or branched chain
hydrocarbon radical containing the indicated number of carbon atoms
and at least one carbon-carbon triple bond (two adjacent sp carbon
atoms). For example, C.sub.2-C.sub.8 alkynyl refers to an alkynyl
group having 1 to 8 (both inclusive) carbon atoms. Examples of
alkynyl include, but are not limited to, ethynyl, 1-propynyl,
3-propynyl and 3-butynyl. Unless stated otherwise, the "alkynyl"
may be unsubstituted or substituted with one or more of the same or
different groups, selected from alkyl, halogen, hydroxy, carboxy,
acetoxy, amino, cyano, nitro, cycloalkyl, alkoxy, aryloxy, aryl,
aralkyl and heterocyclyl.
As used herein, the term "cycloalkyl" whether used alone or as part
of a substituent group, refers to a saturated or partially
unsaturated cyclic hydrocarbon radical including 1, 2 or 3 rings
and including a total of 3 to 14 carbon atoms forming the rings.
The term cycloalkyl includes bridged, fused and spiro ring systems.
For example, C.sub.3-C.sub.8 cycloalkyl refers to a cycloalkyl
group having 3 to 8 (both inclusive) carbon atoms. Examples of
cycloalkyl include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclopentene, adamantyl,
norbornyl, bicyclo[2.1.0]pentane, bicyclo[2.2.1]heptyl,
bicyclo[2.2.1]hept-2-ene, spiro[3.3]heptane and
1,2,3,3a-tetrahydropentalene. Unless stated otherwise, the
"cycloalkyl" may be unsubstituted or substituted with one or more
of the same or different groups selected from halogen, hydroxy,
alkoxy, oxo, alkyl, cycloalkyl, carboxy, acyl, acyloxy, amino,
cyano, nitro, carbonyl, ester, ether, amide, imino, alkylthio, aryl
and heterocyclyl.
As used herein, the term "alkoxy" whether used alone or as part of
a substituent group, refers to an alkyl group as defined above
attached via oxygen linkage to the rest of the molecule. Examples
of alkoxy include, but are not limited to methoxy and ethoxy.
As used herein, the term "haloalkyl" refers to an alkyl group in
which one or more hydrogen atoms are replaced by one or more
halogen atoms. "Halo-C.sub.1-C.sub.8 alkyl" groups have 1 to 8
carbon atoms, "halo-C.sub.1-C.sub.6 alkyl" groups have 1 to 6
carbon atoms. Examples of haloalkyl include, but not limited to,
mono-, di- or tri-fluoromethyl; mono-, di- or tri-chloromethyl;
mono-, di-, tri-, tetra- or pentafluoroethyl; heptafluoropropyl;
difluorochloromethyl and dichlorofluoromethyl.
As used herein, the term "acyl" refers to the group --C(O)R.sub.a,
wherein R.sub.a is alkyl, cycloalkyl, aryl, aralkyl, heteroaryl,
heterocyclyl and heterocyclylalkyl. Unless otherwise stated, the
groups alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl
and heterocyclylalkyl can be unsubstituted or substituted with
halogen, carboxy, cycloalkyl, cyano, amide, alkylthio, thioester,
sulfonyl, nitro, haloalkyl, --OR.sub.x, --SR.sub.x,
--NR.sub.yR.sub.z, --NR.sub.yCOR.sub.z, --CONR.sub.yR.sub.z,
--S(O).sub.mR.sub.y, --S(O).sub.nNR.sub.yR.sub.z,
--NR.sub.ySOR.sub.z, --NR.sub.ySO.sub.2R.sub.z, wherein R.sub.x is
hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;
wherein R.sub.y and R.sub.z are independently selected from
hydrogen, hydroxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,
aryl, aralkyl and heterocyclyl; m is an integer from 0 to 2 and n
is an integer from 0 to 1.
As used herein, the term "aryl" whether used alone or as part of a
substituent group, refers to a monocyclic or polycyclic hydrocarbon
group having 6 to 14 ring carbon atoms, in which the carbocyclic
ring present has a conjugated .pi. electron system. Examples of
aryl include, but are not limited to, phenyl, naphthyl, biphenyl,
fluorenyl and anthracenyl. Unless stated otherwise, the "aryl" may
be unsubstituted or substituted with one or more of the same or
different groups, such as halogen, alkyl, alkenyl, alkynyl,
haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro, acyl,
carboxy, thiol, carbonyl, aryl, cycloalkyl, heteroaryl,
heterocyclyl, --OR.sub.x, --SR.sub.x, --NR.sub.yR.sub.z,
--CONR.sub.yR.sub.z, --NR.sub.yCOR.sub.z,
--NR.sub.yCONR.sub.yR.sub.z, --NR.sub.ySOR.sub.z,
--NR.sub.ySO.sub.2R.sub.z, --S(O).sub.mR.sub.y,
--S(O).sub.nNR.sub.yR.sub.z, wherein R.sub.x is hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl or heterocyclyl; R.sub.y and R.sub.z
are independently selected from hydrogen, hydroxy, alkyl, alkoxy,
alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and
heterocyclyl; m is an integer from 0 to 2 and n is an integer from
0 to 1.
The term "aryloxy" refers to the --O-aryl wherein the term aryl is
as defined above. Exemplary aryloxy groups include, but are not
limited to, phenoxy and naphthoxy.
As used herein, the terms "heterocyclyl" or "heterocyclic" whether
used alone or as part of a substituent group, refers to a
saturated, partially unsaturated, monocyclic or polycyclic ring
system containing 1 to 10 carbon atoms and 1 to 4 identical or
different heteroatoms selected from oxygen, nitrogen and sulfur.
Examples of heterocyclyl include, but are not limited to,
aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl,
azocinyl, dihydrofuranyl, dihydroisoxazolyl, tetrahydrofuranyl,
piperazinyl, morpholinyl, oxazinyl, dihydro-pyridooxazinyl,
tetrahydrothiopyranyl, dihydrobenzofuryl, tetrahydroquinoline,
tetrahydroisoquinoline, benzoxazinyl, phenoxazinyl, phenothiazinyl
and N-oxides thereof. Unless stated otherwise, the "heterocyclyl"
or "heterocyclic" may be unsubstituted or substituted with one or
more of the same or different groups, such as halogen, hydroxy,
cyano, nitro, acyl, oxo, alkyl, alkenyl, alkynyl, haloalkyl,
alkoxy, haloalkoxy, --OR.sub.x, --SR.sub.x,
--C(O)R.sub.y--NR.sub.yR.sub.z, --CONR.sub.yR.sub.z,
--NR.sub.yCOR.sub.z, --NR.sub.yCONR.sub.yR.sub.z,
--NR.sub.ySOR.sub.z, --NR.sub.ySO.sub.2R.sub.z,
--S(O).sub.mR.sub.y, --S(O).sub.nNR.sub.yR.sub.z, aryl, cycloalkyl,
heteroaryl wherein R.sub.x is hydrogen, alkyl, cycloalkyl, aryl,
heteroaryl or heterocyclyl; wherein R.sub.y and R.sub.z are
independently selected from hydrogen, hydroxy, alkyl, alkoxy,
alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and
heterocyclyl; m is an integer from 0 to 2 and n is an integer from
0 to 1.
As used herein, the term "heteroaryl" whether used alone or as part
of a substituent group, refers to aromatic ring structure
containing monocyclic or polycyclic ring system containing 1 to 10
carbon atoms and 1 to 4 identical or different heteroatoms selected
from oxygen, nitrogen and sulfur. Examples of heteroaryl include,
but are not limited to, pyrrolyl, thienyl, furanyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,
triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,
benzoxazolyl, benzothiazolyl, indazolyl, quinolinyl, isoquinolyl,
benzofurazanyl and purinyl. The oxidized form of the ring nitrogen
and sulfur atom of the heteroaryl to provide N-oxide, sulfinyl or
sulfonyl is also encompassed. Unless stated otherwise, the
"heteroaryl" may be unsubstituted or substituted with one or more
of the same or different groups, such as halogen, hydroxy, cyano,
nitro, acyl, oxo, ester, alkyl, alkenyl, alkynyl, haloalkyl,
alkoxy, haloalkoxy, --OR.sub.x, --SR.sub.x,
--C(O)R.sub.y--NR.sub.yR.sub.z, --CONR.sub.yR.sub.z,
--NR.sub.yCOR.sub.z, --NR.sub.yCONR.sub.yR.sub.z,
--NR.sub.ySOR.sub.z, --NR.sub.ySO.sub.2R.sub.z,
--S(O).sub.mR.sub.y, --S(O).sub.nNR.sub.yR.sub.z, aryl, cycloalkyl,
heteroaryl, heterocyclyl, wherein R.sub.x is hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein R.sub.y and
R.sub.z are independently selected from hydrogen, hydroxy, alkyl,
alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl and
heterocyclyl; m is an integer from 0 to 2 and n is an integer from
0 to 1.
As used herein, the term "aralkyl" refers to an alkyl group
substituted with an aryl or heteroaryl group, wherein the terms
alkyl, aryl and heteroaryl are as defined above. Exemplary aralkyl
groups include --(CH.sub.2).sub.p-phenyl,
--(CH.sub.2).sub.p-pyridyl, wherein p is an integer from 1 to 6.
The alkyl, aryl and heteroaryl in the said aralkyl group are as
defined earlier.
As used herein, the term "heteroatom" refers to nitrogen, oxygen
and sulfur. It should be noted that, unless stated otherwise, any
heteroatom with unsatisfied valences is assumed to have a hydrogen
atom to satisfy the valences. The ring heteroatoms can be present
in any desired number and in any position with respect to each
other provided that the resulting heterocyclic system is stable and
suitable as a subgroup in a drug substance.
As used herein, the term "halo" or "halogen" unless otherwise
stated refers to fluorine, chlorine, bromine, or iodine atom.
As used herein, the term "amino" refers to a group of formula
--NH.sub.2, which may be optionally substituted with alkyl,
alkenyl, alkynyl, aryl, heterocyclyl, or cycloalkyl wherein the
terms alkyl, alkenyl, alkynyl, aryl, heterocyclyl and cycloalkyl
are as defined herein above.
As used herein, the term "amide" means --C(O)NH--R', wherein R' is
hydrogen, alkyl, aryl or aralkyl.
As used herein, the term "imino" refers to a group of formula
.dbd.N--R.sub.a, wherein R.sub.a is selected from hydrogen,
hydroxy, alkyl and alkoxy. Examples of such imino radicals include,
but are not limited to, .dbd.NH, .dbd.NCH.sub.3, .dbd.NOH, and
.dbd.NOCH.sub.3.
As used herein, the term "oxo" refers to a .dbd.O moiety.
As used herein, the term "sulfonyl" refers to a --SO.sub.2--
group.
As used herein, the term "carboxy" or "carboxyl" refers to a group
of formula --COOH; also referred to as a carboxylic acid group.
As used herein, the term "carbonyl" whether used alone or as part
of a substituent group, refers to a group of formula
--(C.dbd.O)--.
As used herein, the term "ester" refers to a group of formula
--COOR.sub.a, wherein R.sub.a is an alkyl, cycloalkyl, aryl,
aralkyl, heteroaryl or heterocyclyl as defined above.
As used herein, the term "ether" refers to a group of formula
--R.sub.aOR.sub.a, wherein R.sub.a is independently selected from
alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or heterocyclyl as
defined above.
As used herein, the term "thioester" refers to a group of formula
--R.sub.aSCOR.sub.a, wherein R.sub.a is an alkyl, cycloalkyl, aryl,
aralkyl, heteroaryl or heterocyclyl as defined above.
As used herein, the term "acyloxy" refers to a group of formula
--O-acyl, wherein acyl is as defined above.
As used herein, the term "alkylthio" refers to an alkyl group, as
defined herein, appended to the parent molecular moiety through a
sulfur atom. Examples of alkylthio include, but are not limited,
methylthio, ethylthio, tert-butylthio and hexylthio.
As used herein, the term "pharmaceutically acceptable salts" refers
to non-toxic salts of the compounds of present invention. Salts
derived from inorganic bases include, but are not limited to,
ammonium, calcium, lithium, magnesium, potassium, sodium. Salts
derived from pharmaceutically acceptable organic bases include, but
are not limited to salts of primary, secondary, and tertiary
amines, substituted amines including
[(tris(hydroxymethyl)aminomethane], trimethylamine salts,
diethylamine salts; salts with amino acids such as lysine,
arginine, guanidine and the like. Salts derived from
pharmaceutically acceptable organic and inorganic acids include,
but are not limited to acetate, ascorbate, aspartate,
benzenesulfonate, benzoate, bisulfate, cinnamate, citrate,
fumarate, glutamate, lactate, maleate, malonate, methanesulfonate,
nitrate, oxalate, propionate, phosphate, p-toluenesulfonate,
salicylate, succinate, sulfamate, sulfate, tartrate, hydrochloride,
hydrobromide, hydrofluoride, hydroiodide, trifluoromethanesulfonate
and valproate.
The term "N-oxide" as used herein refers to the oxide of the
nitrogen atom of a nitrogen-containing heteroaryl or heterocycle.
N-oxide can be formed in presence of an oxidizing agent for example
peroxide such as m-chloro-perbenzoic acid or hydrogen peroxide.
As used herein, the term "solvate" describes a complex wherein the
compound is coordinated with a proportional amount of a solvent
molecule. Specific solvates, wherein the solvent is water, are
referred to as hydrates.
As used herein, the term "pharmaceutically acceptable carrier"
refers to a material that is non-toxic, inert, solid, semi-solid or
liquid filler, diluent, encapsulating material or formulation
auxiliary of any type which is compatible with a subject,
preferably a mammal, more preferably a human, and is suitable for
delivering an active agent to the target site without terminating
the activity of the agent.
As used herein, the term "prodrug" refers to a compound, which upon
administration to a subject undergoes chemical conversion by
metabolic or chemical processes to yield a compound of the formula
(I) or a salt and/or solvate thereof. The preferable prodrugs are
Type I, those that are converted intracellularly, more preferably
Type la where the cellular converting location is the site of
therapeutic action. Various forms of prodrugs are well known in the
art and are described in: (a) "Pro-drugs as Novel Delivery
Systems," by T. Higuchi and W. Stella, Vol. 14 of the A.C.S.
Symposium Series, (b) Bioreversible Carriers in Drug Design, ed.
Edward B. Roche, American Pharmaceutical Association and Pergamon
Press, 1987 and (c) Design of Prodrugs, edited by H. Bundgaard,
(Elsevier, 1985).
As used herein, the term "stereoisomer" is a general term used for
all isomers of individual compounds that differ only in the
orientation of their atoms in space. The term stereoisomer includes
mirror image isomers (enantiomers), mixtures of mirror image
isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z)
isomers, and isomers of compounds with more than one chiral center
that are not mirror images of one another (diastereoisomers). The
compounds of the present invention may have asymmetric centers and
occur as racemates, racemic mixtures, individual diastereoisomers,
or enantiomers, or may exist as geometric isomers, with all
isomeric forms of said compounds being included in the present
invention.
As used herein, the term "tautomer" refers to the coexistence of
two (or more) compounds that differ from each other only in the
position of one (or more) mobile atoms and in electron
distribution, for example, keto-enol tautomers.
As used herein, the terms "treat" and "therapy" and the like refer
to alleviate, slow the progression, prophylaxis, modulation,
attenuation or cure of existing disease (e.g., cancer or
inflammation).
The present invention also includes within its scope all
isotopically labeled forms of compounds of formula (I), wherein one
or more atoms of compounds of formula (I) are replaced by their
respective isotopes. Examples of isotopes that may be incorporated
into the compounds disclosed herein include, but are not limited
to, isotopes of hydrogen such as .sup.2H and .sup.3H, carbon such
as .sup.11C, .sup.13C and .sup.14C, nitrogen such as .sup.13N and
.sup.15N, oxygen such as .sup.15O, .sup.17O and .sup.18O, chlorine
such as .sup.36Cl, fluorine such as .sup.18F and sulphur such as
.sup.35S.
Substitution with heavier isotopes, for example, replacing one or
more key carbon-hydrogen bonds with carbon-deuterium bond may show
certain therapeutic advantages, for example, longer metabolism
cycles, improved safety or greater effectiveness.
Isotopically labeled forms of compounds of formula (I), can be
prepared by conventional techniques known to those skilled in the
art or by processes analogous to those described above and in the
subsequent Experimental section by using an appropriate
isotopically labeled reagent instead of non-labeled reagent.
Embodiments
In one embodiment, the present invention provides compounds of
formula (I), wherein, R.sub.a, R.sub.b and R.sub.d are
independently selected from hydrogen, hydroxy, halogen, cyano,
nitro, --COR.sub.1, --COOR.sub.1, --CONH.sub.2, --NR.sub.1R.sub.2,
--C.sub.1-C.sub.8 alkyl, halo-C.sub.1-C.sub.8 alkyl and
--C.sub.1-C.sub.8 alkoxy; R.sub.c is halogen or heteroaryl; R.sub.e
is hydrogen or --C.sub.1-C.sub.8 alkyl; Q is --SO.sub.2,
--C(O)NR.sub.1 or --C(S)NR.sub.1; R.sub.f is
--C.sub.1-C.sub.8alkyl, --(CR.sub.1R.sub.2).sub.p--C.sub.3-C.sub.8
cycloalkyl, --(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--(CR.sub.1R.sub.2).sub.p heterocyclyl, --(CR.sub.1R.sub.2).sub.p
heteroaryl, --C.sub.3-C.sub.8 cycloalkyl, --C.sub.6-C.sub.14 aryl,
heteroaryl or heterocyclyl; R.sub.1 and R.sub.2 are independently
selected from hydrogen and lower alkyl; p is independently an
integer from 1 to 3; with the proviso that when Q is --SO.sub.2,
then R.sub.c is not halogen; wherein each of the above alkyl,
haloalkyl, alkoxy, cycloalkyl, aryl, heterocyclyl and heteroaryl
are unsubstituted or substituted with one or more of the same or
different groups such as halogen, hydroxy, carbonyl, carboxy,
ester, ether, acyl, acyloxy, cyano, amino, amide, imino, alkylthio,
thioester, sulfonyl, nitro, --C.sub.1-C.sub.6 alkyl,
halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.6 alkoxy, --C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.10 aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl group; in all their stereoisomeric and
tautomeric forms and mixtures thereof in all ratios, prodrugs,
N-oxides, and their pharmaceutically acceptable salts and
pharmaceutically acceptable solvates.
In another embodiment, the present invention provides compounds of
formula (I), wherein, R.sub.a, R.sub.b and R.sub.d are
independently selected from hydrogen and --C.sub.1-C.sub.8 alkyl;
R.sub.c is halogen or heteroaryl; R.sub.e is hydrogen or
--C.sub.1-C.sub.8 alkyl; Q is --SO.sub.2, --C(O)NR.sub.1 or
--C(S)NR.sub.1; R.sub.f is --C.sub.1-C.sub.8 alkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--(CR.sub.1R.sub.2).sub.p-heterocyclyl,
--(CR.sub.1R.sub.2).sub.p-heteroaryl, --C.sub.3-C.sub.8 cycloalkyl,
--C.sub.6-C.sub.14 aryl, heteroaryl or heterocyclyl; R.sub.1 and
R.sub.2 are independently selected from hydrogen and lower alkyl; p
is independently an integer from 1 to 3; with the proviso that when
Q is --SO.sub.2, then R.sub.c is not halogen; wherein each of the
above alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl are
unsubstituted or substituted with one or more of the same or
different groups such as halogen, hydroxy, carbonyl, carboxy,
ester, ether, acyl, acyloxy, cyano, amino, amide, imino, alkylthio,
thioester, sulfonyl, nitro, --C.sub.1-C.sub.6 alkyl,
halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.6 alkoxy, --C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.10 aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl; in all their stereoisomeric and
tautomeric forms and mixtures thereof in all ratios, prodrugs,
N-oxides, and their pharmaceutically acceptable salts and
pharmaceutically acceptable solvates.
In another embodiment, the present invention provides compounds of
formula (I), wherein, R.sub.a, R.sub.b and R.sub.d are
independently selected from hydrogen and --C.sub.1-C.sub.4 alkyl;
R.sub.c is halogen or heteroaryl; R.sub.e is hydrogen or
--C.sub.1-C.sub.4 alkyl; Q is --SO.sub.2, --C(O)NH or --C(S)NH;
R.sub.f is --C.sub.1-C.sub.8 alkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--(CR.sub.1R.sub.2).sub.p heterocyclyl, --C.sub.3-C.sub.8
cycloalkyl, --C.sub.6-C.sub.14 aryl, heterocyclyl, or heteroaryl;
R.sub.1 and R.sub.2 are independently selected from hydrogen and
lower alkyl; p is independently an integer from 1 to 3; with the
proviso that when Q is --SO.sub.2, then R.sub.c is not halogen;
wherein each of the above alkyl, cycloalkyl, aryl, heteroaryl and
heterocyclyl are optionally and independently substituted with one
or more of the same or different groups such as halogen, hydroxy,
carbonyl, carboxy, ester, ether, acyl, acyloxy, cyano, amino,
amide, imino, alkylthio, thioester, sulfonyl, nitro,
--C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl,
halo-C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.6alkoxy, --NHCOMe,
--S(O).sub.2Me, aryloxy, heterocyclyl and heteroaryl; in all their
stereoisomeric and tautomeric forms and mixtures thereof in all
ratios, their pharmaceutically acceptable salts, N-oxides,
pharmaceutically acceptable solvates and prodrugs.
In another embodiment, the present invention provides compound of
formula (I), wherein, R.sub.a, R.sub.b and R.sub.d are
independently selected from hydrogen and --C.sub.1-C.sub.4 alkyl;
R.sub.c is halogen or heteroaryl; R.sub.e is hydrogen or
--C.sub.1-C.sub.4 alkyl; Q is --C(O)NH or --C(S)NH; R.sub.f is
--C.sub.1-C.sub.8 alkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--(CR.sub.1R.sub.2).sub.p-- heterocyclyl, --C.sub.3-C.sub.8
cycloalkyl, --C.sub.6-C.sub.14 aryl or heteroaryl; R.sub.1 and
R.sub.2 are independently selected from hydrogen and lower alkyl; p
is independently an integer from 1 to 3; wherein each of the above
alkyl, cycloalkyl, aryl and heteroaryl are optionally and
independently substituted with one or more of the same or different
groups such as halogen, hydroxy, cyano, amino, nitro, alkoxy,
--C.sub.1-C.sub.6 alkyl and halo-C.sub.1-C.sub.6 alkyl; in all
their stereoisomeric and tautomeric forms and mixtures thereof in
all ratios, prodrugs, N-oxides, and their pharmaceutically
acceptable salts and pharmaceutically acceptable solvates.
In another embodiment, the present invention provides compound of
formula (I), wherein, R.sub.a, R.sub.b and R.sub.d are
independently selected from hydrogen and --C.sub.1-C.sub.4 alkyl;
R.sub.c is halogen or heteroaryl; R.sub.e is hydrogen or
--C.sub.1-C.sub.4 alkyl; Q is --C(O)NH or --C(S)NH; R.sub.f is
--(CR.sub.1R.sub.2).sub.p-heterocyclyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl or
--C.sub.6-C.sub.14 aryl; R.sub.1 and R.sub.2 are independently
selected from hydrogen and lower alkyl; p is independently an
integer from 1 to 3; wherein each of the above alkyl, aryl and
heteroaryl are optionally and independently substituted with one or
more of the same or different groups such as halogen, hydroxy,
cyano, amino, nitro, alkoxy, --C.sub.1-C.sub.6 alkyl and
halo-C.sub.1-C.sub.6 alkyl; in all their stereoisomeric and
tautomeric forms and mixtures thereof in all ratios, prodrugs,
N-oxides, and their pharmaceutically acceptable salts and
pharmaceutically acceptable solvates.
In another embodiment, the present invention provides compound of
formula (I), wherein, R.sub.a, R.sub.b and R.sub.d are
independently selected from hydrogen and --C.sub.1-C.sub.4 alkyl;
R.sub.c is halogen; R.sub.e is hydrogen or --C.sub.1-C.sub.4 alkyl;
Q is --C(O)NH or --C(S)NH; R.sub.f is
--(CR.sub.1R.sub.2).sub.p-heterocyclyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl or
--C.sub.6-C.sub.14 aryl; R.sub.1 and R.sub.2 are independently
selected from hydrogen and lower alkyl; p is independently an
integer from 1 to 3; wherein each of the above alkyl, aryl and
heteroaryl are optionally and independently substituted with one or
more of the same or different groups such as halogen, hydroxy,
cyano, amino, nitro, alkoxy, --C.sub.1-C.sub.6 alkyl and
halo-C.sub.1-C.sub.6 alkyl; in all their stereoisomeric and
tautomeric forms and mixtures thereof in all ratios, their
pharmaceutically acceptable salts, N-oxides, pharmaceutically
acceptable solvates and prodrugs.
In another embodiment, the present invention provides compounds of
formula (I), wherein, R.sub.a, R.sub.b and R.sub.d are
independently selected from hydrogen and --C.sub.1-C.sub.4 alkyl;
R.sub.c is heteroaryl; R.sub.e is hydrogen or --C.sub.1-C.sub.4
alkyl; Q is --SO.sub.2, --C(O)NR.sub.1 or --C(S)NR.sub.1; R.sub.f
is --C.sub.1-C.sub.8 alkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--(CR.sub.1R.sub.2).sub.p-heterocyclyl,
--(CR.sub.1R.sub.2).sub.p-heteroaryl, --C.sub.3-C.sub.8 cycloalkyl,
--C.sub.6-C.sub.14 aryl, heteroaryl or heterocyclyl; R.sub.1 and
R.sub.2 are independently selected from hydrogen and lower alkyl; p
is independently an integer from 1 to 3; wherein each of the above
alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally
and independently substituted with one or more of the same or
different groups such as halogen, hydroxy, carbonyl, carboxy,
ester, ether, acyl, acyloxy, cyano, amino, amide, imino, alkylthio,
thioester, sulfonyl, nitro, --C.sub.1-C.sub.6 alkyl,
halo-C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.10 aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl; in all their stereoisomeric and
tautomeric forms and mixtures thereof in all ratios, prodrugs,
N-oxides, and their pharmaceutically acceptable salts and
pharmaceutically acceptable solvates.
In another embodiment, the present invention provides compound of
formula (I), wherein, R.sub.a, R.sub.b and R.sub.d are
independently selected from hydrogen and --C.sub.1-C.sub.4 alkyl;
R.sub.c is heteroaryl; R.sub.e is hydrogen or --C.sub.1-C.sub.4
alkyl; Q is --SO.sub.2, --C(O)NH or --C(S)NH; R.sub.f is
--C.sub.1-C.sub.8 alkyl, --(CH.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--(CH.sub.2).sub.p-- heterocyclyl, --(CH.sub.2).sub.p-heteroaryl,
--C.sub.3-C.sub.8 cycloalkyl, --C.sub.6-C.sub.14 aryl, heteroaryl
or heterocyclyl; R.sub.1 and R.sub.2 are independently selected
from hydrogen and lower alkyl; p is independently an integer from 1
to 3; wherein each of the above alkyl, aryl, heterocyclyl and
heteroaryl are optionally and independently substituted with one or
more of the same or different groups such as halogen, hydroxy,
carbonyl, carboxy, ester, ether, acyl, acyloxy, cyano, amino,
amide, imino, alkylthio, thioester, sulfonyl, nitro,
--C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.10 aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl; in all their stereoisomeric and
tautomeric forms and mixtures thereof in all ratios, prodrugs,
N-oxides, and their pharmaceutically acceptable salts and
pharmaceutically acceptable solvates.
In another embodiment, the present invention provides compounds of
formula (I), R.sub.a, R.sub.b and R.sub.d are independently
selected from hydrogen and methyl; R.sub.c is halogen or heteroaryl
selected from pyridyl, quinolinyl, indolyl, pyrimidinyl and
pyrrolyl wherein each of pyridyl, quinolinyl, indolyl, pyrimidinyl
and pyrrolyl is optionally substituted with one or more halogen,
--C.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-alkoxy, and
halo-C.sub.1-C.sub.6-alkyl; R.sub.e is hydrogen or
--C.sub.1-C.sub.4 alkyl; Q is --SO.sub.2, --C(O)NH or --C(S)NH;
R.sub.f is --C.sub.1-C.sub.8 alkyl,
--(CH.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--(CH.sub.2).sub.p-heterocyclyl, --C.sub.3-C.sub.8-cycloalkyl,
--C.sub.6-C.sub.14 aryl, heterocyclyl or heteroaryl; p is
independently an integer from 1 to 3; R.sub.1 and R.sub.2 are
independently selected from hydrogen and lower alkyl; with the
proviso that when Q is --SO.sub.2, then R.sub.c is not halogen;
wherein each of the above alkyl, cycloalkyl, aryl, heteroaryl and
heterocyclyl are optionally and independently substituted with one
or more of the same or different groups such as halogen, hydroxy,
carbonyl, carboxy, ester, ether, acyl, acyloxy, cyano, amino,
amide, imino, alkylthio, thioester, sulfonyl, nitro,
--C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl,
halo-C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.6alkoxy,
--C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.10 aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl group; in all their stereoisomeric and
tautomeric forms and mixtures thereof in all ratios, their
pharmaceutically acceptable salts, N-oxides, pharmaceutically
acceptable solvates and prodrugs.
In another embodiment, the present invention provides compounds of
formula (I), wherein, R.sub.a, R.sub.b and R.sub.d are
independently selected from hydrogen and --C.sub.1-C.sub.4 alkyl;
R.sub.c is heteroaryl; R.sub.e is hydrogen or --C.sub.1-C.sub.4
alkyl; Q is --SO.sub.2; R.sub.f is --C.sub.1-C.sub.8 alkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.14 aryl, --C.sub.3-C.sub.8
cycloalkyl, --C.sub.6-C.sub.14 aryl, heteroaryl or heterocyclyl; p
is independently an integer from 1 to 3; R.sub.1 and R.sub.2 are
independently selected from hydrogen and lower alkyl; wherein each
of the above alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl
are unsubstituted or substituted with one or more of the same or
different groups such as halogen, hydroxy, carbonyl, carboxy,
ester, ether, acyl, acyloxy, cyano, amino, amide, imino, alkylthio,
thioester, sulfonyl, nitro, --C.sub.1-C.sub.6 alkyl,
halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.6alkoxy, --C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.10 aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl group; in all their stereoisomeric and
tautomeric forms and mixtures thereof in all ratios, their
pharmaceutically acceptable salts, pharmaceutically acceptable
solvates, prodrugs and N-oxides.
In another embodiment, the present invention provides compounds of
formula (I), wherein, R.sub.a, R.sub.b and R.sub.d are
independently selected from hydrogen and methyl; R.sub.c is
heteroaryl selected from indolyl, pyrrolyl, pyridyl, pyrimidinyl
and quinolinyl, wherein each of indolyl, pyrrolyl, pyridyl,
pyrimidinyl and quinolinyl is optionally substituted with one or
more groups selected from halogen, --C.sub.1-C.sub.6-alkyl,
--C.sub.1-C.sub.6-alkoxy, and halo-C.sub.1-C.sub.6-alkyl; R.sub.e
is hydrogen or --C.sub.1-C.sub.4 alkyl; Q is --SO.sub.2; R.sub.f is
--C.sub.1-C.sub.8 alkyl, --(CH.sub.2).sub.p--C.sub.6-C.sub.14 aryl,
--C.sub.3-C.sub.8 cycloalkyl, --C.sub.6-C.sub.14 aryl, heteroaryl
or heterocyclyl; p is independently an integer from 1 to 3; R.sub.1
and R.sub.2 are independently selected from hydrogen and lower
alkyl; wherein each of the above alkyl, cycloalkyl, aryl,
heterocyclyl and heteroaryl are unsubstituted or substituted with
one or more of the same or different groups such as halogen,
hydroxy, carbonyl, carboxy, ester, ether, acyl, acyloxy, cyano,
amino, amide, imino, alkylthio, thioester, sulfonyl, nitro,
--C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl,
halo-C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.6alkoxy,
--C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.10 aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl group; in all their stereoisomeric and
tautomeric forms and mixtures thereof in all ratios, their
pharmaceutically acceptable salts, pharmaceutically acceptable
solvates, prodrugs and N-oxides.
In another embodiment, the present invention provides compounds of
formula (I), R.sub.a, R.sub.b and R.sub.d are independently
selected from hydrogen and methyl; R.sub.c is halogen or heteroaryl
selected from pyridyl, quinolinyl, indolyl, pyrimidinyl and
pyrrolyl wherein each of pyridyl, quinolinyl, indolyl, pyrimidinyl
and pyrrolyl is optionally substituted with one or more halogen,
--C.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-alkoxy, and
halo-C.sub.1-C.sub.6-alkyl; R.sub.e is hydrogen or
--C.sub.1-C.sub.4 alkyl; Q is --SO.sub.2, --C(O)NH or --C(S)NH;
R.sub.f is hexyl, --(CH.sub.2)-phenyl, --(CH.sub.2)-2-morpholinyl,
cyclohexyl, phenyl, thiophenyl, imidazolyl, pyrrolyl, furanyl,
dihydro-pyridooxazinyl or quinolinyl; wherein each of hexyl,
--(CH.sub.2)-- phenyl, --(CH.sub.2)-2-morpholinyl, cyclohexyl,
phenyl, thiophenyl, imidazolyl, pyrrolyl, furanyl,
dihydro-pyridooxazinyl and quinolinyl are optionally and
independently substituted with one or more of the same or different
groups such as halogen, hydroxy, carbonyl, carboxy, ester, ether,
acyl, acyloxy, cyano, amino, amide, imino, alkylthio, thioester,
sulfonyl, nitro, --C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6
alkyl, halo-C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.6 alkoxy,
--C.sub.3-C.sub.8 cycloalkyl,
--(CR.sub.1R.sub.2).sub.p--C.sub.6-C.sub.10 aryl,
--C.sub.6-C.sub.10 aryl, --NHCOMe, --S(O).sub.2Me, aryloxy,
heterocyclyl and heteroaryl group; R.sub.1 and R.sub.2 are
independently selected from hydrogen and lower alkyl; p is
independently an integer from 1 to 3; with the proviso that when Q
is --SO.sub.2, then R.sub.c is not halogen; in all their
stereoisomeric and tautomeric forms and mixtures thereof in all
ratios, their pharmaceutically acceptable salts, N-oxides,
pharmaceutically acceptable solvates and prodrugs.
In another embodiment, the present invention provides compounds of
formula (I), R.sub.a, R.sub.b and R.sub.d are independently
selected from hydrogen and methyl; R.sub.c is halogen,
pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3yl,
5-fluoropyridin-3yl, 5-trifluoromethylpyridin-3yl,
6-chloropyridin-3yl, 6-fluoropyridin-3yl,
6-fluoro-5-methylpyridin-3yl, 6-methylpyridin-3yl,
6-methoxypyridin-3y1, quinolinyl, 2-indolyl,
1-methyl-1H-indol-3-yl, pyrimidin-5-yl,
2,4-dimethoxypyrimidin-5-yl, 2-methoxypyrimidin-5-yl, and
1H-pyrrol-2-yl; R.sub.e is hydrogen or --C.sub.1-C.sub.4 alkyl; Q
is --SO.sub.2, --C(O)NH or --C(S)NH; R.sub.f is hexyl,
--(CH.sub.2)-phenyl, --(CH.sub.2).sub.2-morpholinyl, cyclohexyl,
phenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,
2,5-dibromophenyl, 2-bromo-4-fluorophenyl,
2-bromo-5-trifluoromethylphenyl, 2-bromo-4,6-difluorophenyl,
4-bromo-2,5-difluorophenyl, 4-bromo-2,6-difluorophenyl,
4-bromo-2,6-dichlorophenyl, 4-bromo-3-methylphenyl,
4-bromo-2-chlorophenyl, 4-bromo-2-trifluoromethoxyphenyl,
5-bromo-2-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl,
2-chloro-4-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl,
2-chloro-4-fluorophenyl, 3-chloro-2-fluorophenyl,
3-chloro-4-fluoro-phenyl, 3-chloro-2-methylphenyl,
4-chloro-3-nitrophenyl, 4-chloro-2,5-dimethylphenyl,
5-chloro-2-methoyphenyl, 5-chloro-2-fluorophenyl, 2-cyanophenyl,
3-cyanophenyl, 3-cyano-4-fluorophenyl, 4-cyanophenyl,
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl,
2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl,
3,5-difluorophenyl, 2-fluoro-5-methylphenyl,
3-fluoro-4-methylphenyl, 4-fluoro-2-methylphenyl,
5-fluoro-2-methylphenyl, 5-fluoro-2-methoxyphenyl,
2,3,4-trifluorophenyl, 4-iodophenyl, 2-methylphenyl,
2-methylsulfonylphenyl, 2-methyl-5-nitrophenyl, 3-methylphenyl,
4-methylphenyl, 2,5-dimethylphenyl, 2-methyl-5-carboxyphenyl,
2,4,6-trimethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl,
2,5-dimethoxyphenyl, 2-methoxy-5-amidophenyl,
2-methoxy-4-methylphenyl, 2-methoxy-5-methylphenyl,
2-methoxy-6-methylphenyl, 3-trifluoromethylphenyl,
2-trifluoromethoxyphenyl, 3,5-bis(trifluoromethyl)phenyl,
2-nitrophenyl, 3-nitrophenyl, 2-phenoxyphenyl, 4-phenoxyphenyl,
4-acetamidophenyl, 2-morpholino-5-trifluoromethylphenyl,
2-methyl-5-methylsulfonylphenyl, benzyl, biphenyl-4-yl,
2'-fluoro-5'-(trifluoromethyl)biphenyl, thiophen-2-yl,
quinolin-8-yl, 1,2-dimethyl-imidazol-4-yl, cyclohexyl,
pyridin-3-yl, 6-morpholino-pyridin-3-yl,
methyl(1-methyl-pyrrol-2-yl)-2-carboxylate,
3,4-dihydro-4-methyl-pyrido[3,2-b][1,4]oxazine-7-yl,
methyl(thiophen-3-yl)-2-carboxylate,
methyl(furan-5-yl)-2-carboxylate or 2-morpholinoethyl; p is
independently an integer from 1 to 3; with the proviso that when Q
is --SO.sub.2, then R.sub.c is not halogen; in all their
stereoisomeric and tautomeric forms and mixtures thereof in all
ratios, their pharmaceutically acceptable salts, N-oxides,
pharmaceutically acceptable solvates and prodrugs.
Representative compounds of the present invention include any of
the following compounds or their pharmaceutically acceptable salts
and solvates as well as stereoisomers and tautomers thereof.
However, the present invention is not limited to these compounds
alone:
N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)
benzenesulfonohydrazide; N, 3-dimethyl-N'-((6-pyridin-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide; N,
4-dimethyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
2-Fluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
3-Fluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)benzenesulfonohydrazide;
4-Fluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
3-Bromo-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
4-Bromo-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
2-Cyano-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
(E)-3-cyano-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene) benzenesulfonohydrazide;
4-Cyano-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
4-Methoxy-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
2,4-Difluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)benzenesulfonohydrazide;
2,6-Difluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)benzenesulfonohydrazide;
3,4-difluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
3,5-Difluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)benzenesulfonohydrazide;
3-Chloro-2-fluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)benzenesulfonohydrazide;
3-Chloro-4-fluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)benzenesulfonohydrazide;
2-Fluoro-N, 5-dimethyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)benzenesulfonohydrazide;
3-Fluoro-N, 4-dimethyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)benzenesulfonohydrazide;
5-Fluoro-N, 2-dimethyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl) methylene)benzenesulfonohydrazide;
3-(3-((2-(5-fluoro-2-methylphenylsulfonyl)-2-methylhydrazono)methyl)imida-
zo[1,2-a]pyridin-6-yl)pyridine 1-oxide; 4-Bromo-N,
3-dimethyl-N'-((6-(pyridine-3-yl) imidazo[1,2-a]pyridine-3-yl)
methylene)benzenesulfonohydrazide; N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)-3,5-bis
(trifluoromethyl)benzenesulfonohydrazide;
3-Cyano-4-fluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl) methylene)benzenesulfonohydrazide; N,
2-dimethyl-5 nitro-N'-((6-pyridin-3-yl)
imidazo[1,2-a]pyridine-3-yl) methylene)benzenesulfonohydrazide;
2-Bromo-4,6-difluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl) methylene)benzenesulfonohydrazide; N,
2,4,6-tetramethyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
N-methyl-1-phenyl-N'-((6-pyridin-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)thiophene-2-sulfonohydrazide;
N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)
quinoline-8-sulfonohydrazide; N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) cyclohexanesulfonohydrazide;
3-Fluoro-N, 4-dimethyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
3-Cyano-4-fluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl) methylene)benzenesulfonohydrazide;
(E)-2,3,4-Trifluoro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-
-yl)methylene)benzenesulfonohydrazide; (E)-4-bromo-2,5-difluoro
--N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)benz-
enesulfonohydrazide;
(E)-2-bromo-4-fluoro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl) methylene)benzenesulfonohydrazide;
(E)-N-methyl-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-3-(trifluoromethyl)benzenesulfonohy-
drazide; (E)-4-bromo-2,6-dichloro-N-methyl-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide;
(E)-3-chloro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)
methylene)benzenesulfonohydrazide;
(E)-2-chloro-N-methyl-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-4-(trifluoromethyl)benzenesulfonohy-
drazide; (E)-2-chloro-4-fluoro-N-methyl-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
(E)-N, 1,2-trimethyl-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-1H-imidazole-4-sulfonohydrazide;
(E)-4-chloro-N, 2,5-trimethyl-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
(E)-2,5-difluoro-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
(E)-5-fluoro-2-methoxy-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridi-
n-3-yl)methylene)benzenesulfonohydrazide;
(E)-4-Iodo-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methy-
lene)benzenesulfonohydrazide;
(E)-2'-Fluoro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)me-
thylene)-5'-(trifluoromethyl)biphenyl-4-sulfonohydrazide;
4-Methyl-3-(1-methyl-2-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) hydrazinylsulfonyl)benzoic
acid;
4-Methoxy-3-(1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)hydrazinylsulfonyl)benzamide; (E)-N,
2,5-trimethyl-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
(E)-2,5-dibromo-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
(E)-2,5-dimethoxy-N-methyl-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
(E)-N, 2-dimethyl-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
(E)-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-2-(trifluoromethoxy)benzenesulfonoh-
ydrazide; (E)-5-chloro-2-methoxy-N-methyl-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
(E)-4-bromo-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-2-(trifluoromethoxy)benzenesulfonoh-
ydrazide; (E)-2-bromo-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-5-(trifluoromethyl)benzenesulfonohy-
drazide; (E)-N-methyl-2-nitro-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
(E)-N-methyl-2-(methylsulfonyl)-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
(E)-N-methyl-2-phenoxy-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
(E)-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) hexane-1-sulfonohydrazide;
(E)-N-methyl-2-morpholino-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-5-(trifluoromethyl)benzenesulfonohy-
drazide; (E)-N,2-dimethyl-5-(methylsulfonyl)-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
(E)-2-bromo-N-methyl-N-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
(E)-2-chloro-N-methyl-N-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-5-(trifluoromethyl)benzenesulfonohy-
drazide; (E)-N-methyl-6-morpholino-N-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) pyridine-3-sulfonohydrazide;
(E)-Methyl 1-methyl-5-(1-methyl-2-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)
methylene)hydrazinylsulfonyl)-1H-pyrrole-2-carboxylate;
(E)-N,4-dimethyl-N-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-3,4-dihydro-2H-pyrido[3,2-b][1,4]ox-
azine-7-sulfonohydrazide; (E)-N-methyl-N-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) pyridine-3-sulfonohydrazide;
(E)-N-methyl-4-phenoxy-N-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
(E)-Methyl
3-(1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)
hydrazinylsulfonyl)thiophene-2-carboxylate;
(E)-N-methyl-N-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) biphenyl-4-sulfonohydrazide;
(E)-Methyl 5-(1-methyl-2-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) hydrazinylsulfonyl)
furan-2-carboxylate;
(E)-4-chloro-N-methyl-3-nitro-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
(E)-5-bromo-2-methoxy-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
(E)-3-chloro-N, 2-dimethyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
(E)-5-chloro-2-fluoro-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
(E)-4-Fluoro-N, 2-dimethyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
(E)-2-methoxy-N, 6-dimethyl-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
(E)-4-Bromo-2-chloro-N-methyl-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
(E)-2-chloro-N-methyl-N'((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
(E)-N-(4-(1-methyl-2-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)
hydrazinylsulfonyl)phenyl)acetamide; N'-((6-(6-fluoropyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)-n,
2-dimethyl-5-nitrobenzenesulfonohydrazide;
(E)-N-ethyl-2-methyl-5-nitro-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-
-yl) methylene)benzenesulfonohydrazide; N,
2-dimethyl-5-nitro-N'-((6-(pyridine-4-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
5-Fluoro-N, 2-dimethyl-N'-((6-(pyridine-4-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
(E)-5-Fluoro-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)-N,2-dimethylbenzenesulfonohydrazide;
(E)-5-Fluoro-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)-2-methoxy-N-methylbenzenesulfonohydrazide;
(E)-3-fluoro-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-N-methylbenzenesulfonohydrazide;
(E)-5-chloro-2-fluoro-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl)methylene)-N-methylbenzenesulfonohydrazide;
(E)-5-bromo-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-2-methoxy-N-methylbenzenesulfonohyd-
razide; (E)-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-2,5-dimethoxy-N-methylbenzenesulfon-
ohydrazide; (E)-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-N,
2-dimethyl-5-(methylsulfonyl)benzenesulfonohydrazide;
(E)-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-N-methylhexane-1-sulfonohydrazide;
(E)-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-2-methoxy-N,
4-dimethylbenzenesulfonohydrazide;
(E)-2-bromo-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-N-methylbenzenesulfonohydrazide;
(E)-2-cyano-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-N-methylbenzenesulfonohydrazide;
(E)-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-2-methoxy-N,5-dimethylbenzenesulfon-
ohydrazide; N, 2-Dimethyl-5-nitro-N'((6-(quinolin-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide;
(E)-5-Fluoro-N,2-dimethyl-N'-((8-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide;
(E)-3,5-Difluoro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyr-
idin-3-yl)methylene)benzenesulfonohydrazide;
(E)-4-Bromo-2,6-difluoro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1-
,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide;
(E)-N,3-dimethyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl-
)methylene)benzenesulfonohydrazide;
(E)-2-cyano-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl)methylene)benzenesulfonohydrazide;
(E)-3-cyano-4-fluoro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a-
]pyridin-3-yl)methylene)benzenesulfonohydrazide;
(E)-3-cyano-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl)methylene)benzenesulfonohydrazide;
(E)-4-Bromo-N,3-dimethyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyri-
din-3-yl)methylene)benzenesulfonohydrazide;
(E)-3-Methoxy-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridi-
n-3-yl)methylene)benzenesulfonohydrazide;
(E)-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)met-
hylene)-3-nitrobenzenesulfonohydrazide;
(E)-3-Chloro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-
-3-yl)methylene)benzenesulfonohydrazide;
(E)-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)met-
hylene)-3-(trifluoromethyl)benzenesulfonohydrazide;
(E)-2-Bromo-4,6-difluoro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1-
,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide;
(E)-4-Chloro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-
-3-yl)methylene)-3-nitrobenzenesulfonohydrazide;
(E)-2-Bromo-4-fluoro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a-
]pyridin-3-yl)methylene)benzenesulfonohydrazide;
(E)-N'-((6-(1H-indol-2-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-5-fluoro--
N,2-dimethylbenzenesulfonohydrazide;
(E)-5-fluoro-N,2-dimethyl-N'-((6-(1-methyl-1H-indol-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide;
2-Cyano-N-methyl-N'((7-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
5-Fluoro-N, 2-dimethyl-N'-((7-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide; N,
3-dimethyl-N'-((7-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
3-Fluoro-N-methyl-N'-((7-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
3-Chloro-N-methyl-N'-((7-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-y-
l)methylene)benzenesulfonohydrazide;
N-methyl-N'-((7-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-3-(trifluoromethyl)benzenesulfonohy-
drazide; 3-Bromo-N-methyl-N'((7-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide;
5-Fluoro-N,
2-dimethyl-N'-((7-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)
methylene)benzenesulfonohydrazide;
N'-((6-(2,4-dimethoxypyrimidin-5-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-5-fluoro-N,
2-dimethylbenzenesulfonohydrazide;
(E)-5-Fluoro-N,2-dimethyl-N'-((5-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyr-
idin-3-yl)methylene)benzenesulfonohydrazide;
(E)-N,3-dimethyl-N'-((5-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl-
)methylene)benzenesulfonohydrazide;
(E)-5-fluoro-N,2-dimethyl-N'-((6-(6-methylpyridin-3-yl)imidazo[1,2-a]pyri-
din-3-yl)methylene)benzenesulfonohydrazide;
(E)-N-methyl-N'-((6-(6-methylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)-2-(trifluoromethoxy)benzenesulfonohydrazide;
(E)-5-Fluoro-2-methoxy-N-methyl-N'-((6-(6-methylpyridin-3-yl)imidazo[1,2--
a]pyridin-3-yl)methylene)benzenesulfonohydrazide;
(E)-N,2-dimethyl-N'-((6-(6-methylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)-
methylene)benzenesulfonohydrazide;
(E)-5-fluoro-N'-((6-(5-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-N,
2-dimethylbenzenesulfonohydrazide;
(E)-5-Fluoro-N'-((6-(5-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-2-methoxy-N-methylbenzenesulfonohyd-
razide;
(E)-5-Fluoro-N'-((6-(6-fluoro-5-methylpyridin-3-yl)imidazo[1,2-a]p-
yridin-3-yl)methylene)-N,2-dimethylbenzenesulfonohydrazide;
(E)-N'-((6-(6-Chloropyridins-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-5-
-fluoro-N,2-dimethylbenzenesulfonohydrazide;
(E)-N'-((6-(1H-Pyrrol-2-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-5-fluoro-
-N,2-dimethylbenzenesulfonohydrazide;
(E)-5-fluoro-N'-((6-(6-methoxypyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)met-
hylene)-N,2-dimethylbenzenesulfonohydrazide;
(E)-5-Fluoro-N-((6-(2-methoxypyrimidin-5-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)-N,
2-dimethylbenzenesulfonohydrazide; (E)-5-fluoro-N,
2-dimethyl-N'-((6-(5-(trifluoromethyl)pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide;
(E)-5-Fluoro-N,
2-dimethyl-N'-((6-(pyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)methylene)be-
nzenesulfonohydrazide;
(E)-N-benzyl-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)hydrazinecarboxamide;
(E)-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-N--
p-tolylhydrazinecarboxamide;
(E)-N-(2-fluoro-5-methylphenyl)-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2--
a]pyridin-3-yl)methylene)hydrazinecarboxamide;
(E)-N-(5-fluoro-2-methylphenyl)-1-methyl-2-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)hydrazinecarboxamide;
N-benzyl-2-((6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-1-methylhydrazi-
necarboxamide;
(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-N-(2-fluoro-5-methylphenyl)-
-1-methylhydrazinecarboxamide;
(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-N-(5-fluoro-2-methylphenyl)-
-1-methylhydrazinecarboxamide;
(E)-1-methyl-N-(2-morpholinoethyl)-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyri-
din-3-yl)methylene)hydrazinecarbothioamide;
(E)-N-(4-cyanophenyl)-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl)methylene)hydrazinecarbothioamide;
(E)-N-(4-methoxyphenyl)-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridi-
n-3-yl)methylene)hydrazinecarbothioamide;
2-((6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-1-methyl-N-(2-morpholino-
ethyl) hydrazinecarbothioamide;
2-((6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-1-methyl-N-(4-(trifluoro-
methyl)phenyl) hydrazinecarbothioamide; or their pharmaceutically
acceptable salts and solvates.
According to a further aspect of the present invention, there is
provided a process for the preparation of a compound of formula
(I)
##STR00003## wherein, Q is SO.sub.2; R.sub.a, R.sub.b and R.sub.d
are hydrogen or methyl; R.sub.c, R.sub.e and R.sub.f are as defined
for formula (I), which comprises, refluxing a compound of formula
(3)
##STR00004## with a compound of formula H.sub.2N--NH--R.sub.e in
presence of alcoholic solvent followed by reacting with a compound
of formula R.sub.fSO.sub.2X, wherein Q is SO.sub.2; X is halogen,
R.sub.a, R.sub.b and R.sub.d are hydrogen or methyl, R.sub.c,
R.sub.e and R.sub.f are as defined above for formula (I) in
presence of a base, such as pyridine; and optionally converting the
resulting compound into a pharmaceutically acceptable salt.
According to a further aspect of the present invention, there is
provided a process for the preparation of a compound of formula
(I)
##STR00005## wherein, Q is --C(O)NH or --C(S)NH; R.sub.a, R.sub.b
and R.sub.d are hydrogen or methyl, R.sub.c, R.sub.e and R.sub.f
are as defined for formula (I), which comprises, refluxing a
compound of formula (3)
##STR00006## with a compound of formula H.sub.2N--NH--R.sub.e in
presence of an alcoholic solvent followed by reacting with a
compound of formula O.dbd.C.dbd.N.dbd.R.sub.f or
S.dbd.C.dbd.N.dbd.R.sub.f, wherein R.sub.a, R.sub.b and R.sub.d are
hydrogen or methyl, R.sub.c, R.sub.e and R.sub.f are as defined
above for formula (I); and optionally converting the resulting
compound into a pharmaceutically acceptable salt.
A convenient method for the synthesis of a compound of the present
invention typically involves the series of steps described herein
below:
The compounds of formula (I) are prepared using techniques known to
one skilled in the art through the reaction sequences shown in the
Schemes 1-2. Those with skill in the art will appreciate that the
specific starting compounds and reagents, such as acids, bases,
solvents, etc., identified in the schemes can be altered to prepare
compounds encompassed by the present invention.
Schemes
The compounds of the present invention also include all
stereoisomeric forms and mixtures thereof in all ratios and their
pharmaceutically acceptable salts, solvates and polymorphs.
Furthermore, all the compounds of the present invention are a
subject of the present invention in the form of their prodrugs and
other derivatives.
According to another aspect of present invention, the
imidazo[1,2-a]pyridine derivatives of formula (I) can be prepared
in a number of ways using methods well known to the person skilled
in the art. Examples of methods to prepare the present compounds
are described below and illustrated in Schemes 1 and 2 but are not
limited thereto. It will be appreciated by persons skilled in the
art that within certain of the processes described herein, the
order of the synthetic steps employed may be varied and will depend
inter alia on factors such as the nature of functional groups
present in a particular substrate and the protecting group strategy
(if any) to be adopted clearly, such factors will also influence
the choice of reagent to be used in the synthetic steps. Although
specific starting materials, reagents and reaction conditions are
revealed in the schemes and the description below, other starting
materials, reagents and reaction conditions can be used to obtain
the compounds of formula (I).
The reagents, reactants and intermediates used in the following
processes are either commercially available or can be prepared
according to standard literature procedures known in the art. The
starting compounds and the intermediates used for the synthesis of
compounds of the present invention, are referred to with general
symbols namely (1), (2), (3) and (4). The process used in schemes 1
and 2 of the present invention, is referred to with general symbols
namely 1a, 1b, 1c, 1d, 1e, if and 1 g.
Processes for the preparation of compounds of the present invention
are set forth in the following schemes:
##STR00007## wherein X is halogen, R.sub.a, R.sub.b and R.sub.d are
hydrogen; R.sub.c, R.sub.e and R.sub.f are as defined for formula
(I). Reaction Conditions 1a: HC(O)--CH(X)--CH(O), reflux, 1 to 2
hours; 1b: R.sub.e--B(OH).sub.2, 100-120.degree. C., 3 to 4 hours;
1c: a) H.sub.2N--NH--R.sub.e, reflux, 85.degree. C., 2 to 3 hours;
b) R.sub.fSO.sub.2X, room temperature, 1 to 2 hours;
The compound of formula (2) can be prepared by refluxing compound
of formula (I) with a compound of formula HC(O)--CH(X)--CH(O) in an
appropriate solvent such as acetonitrile, dimethylformamide,
dimethylsulfoxide or a mixture thereof. The compound of formula (2)
can be refluxed with a boronic acid derivative of formula
R.sub.c--B(OH).sub.2 in presence of a base such as sodium
carbonate, potassium carbonate, cesium carbonate, sodium
bicarbonate, potassium bicarbonate or a mixture thereof and a
catalyst such as dichlorobis(triphenylphosphine) palladium (II) in
an appropriate solvent such as dimethylformamide,
dimethylsulfoxide, tetrahydrofuran or a mixture thereof to form a
compound of formula (3). The compound of formula (3) can be
refluxed with a compound of formula H.sub.2N--NH--R.sub.e in a
polar solvent such as ethanol, methanol, isopropanol or mixture
thereof to form the corresponding hydrazide. The hydrazide so
formed can be treated with compound of formula R.sub.fSO.sub.2X in
presence of a base, such as pyridine, triethylamine, ammonia or
mixture thereof to form a compound of formula (I).
##STR00008## wherein, R.sub.a, R.sub.b and R.sub.d are hydrogen or
methyl; R.sub.c is halogen or heteroaryl; Q is --C(O)NH or
--C(S)NH; R.sub.e and R.sub.f are as defined earlier for formula
(I). Reaction Conditions 1d: a) NH.sub.2NH-Me, 85.degree. C., 1.5
hours, b) O.dbd.C.dbd.N.dbd.R.sub.f or S.dbd.C.dbd.N.dbd.R.sub.f,
reflux, 2 hours
The compound of formula (3) can be reacted with methyl hydrazine in
an appropriate solvent such as ethanol to obtain a hydrazine
intermediate. The hydrazine so formed can be refluxed for about 2
hours with compound of formula O.dbd.C.dbd.N.dbd.R.sub.f or
S.dbd.C.dbd.N.dbd.R.sub.f to obtain a compound of formula (I),
wherein, R.sub.a, R.sub.b and R.sub.d are hydrogen or methyl;
R.sub.c is halogen or heteroaryl; Q is --C(O)NH or --C(S)NH and
R.sub.e and R.sub.f are as defined earlier.
It will be appreciated by those skilled in the art that the
compounds of the present invention may also be utilized in the form
of their pharmaceutically acceptable salts or solvates. The
pharmaceutically acceptable salts of the compounds of the present
invention are non-toxic and can be used physiologically.
The pharmaceutically acceptable salts of the present invention can
be synthesized from the subject compound, which contains a basic or
an acidic moiety, by conventional chemical methods. Generally the
salts are prepared by contacting the free base or acid with
required amount of the desired salt-forming inorganic or organic
acid or base in a suitable solvent or dispersant or from another
salt by cation or anion exchange. Suitable solvents are, for
example, ethyl acetate, ether, alcohols, acetone, tetrahydrofuran
(THF), dioxane or mixtures of these solvents.
When the compounds of the present invention represented by the
formula (I) contain one or more basic groups, i.e. groups which can
be protonated, they can form an addition salt with an inorganic or
organic acid. Examples of suitable inorganic acid salts include,
but are not limited to, hydrochloride, hydrobromide, hydrofluoride,
sulfate, sulfamate, phosphate, nitrate and bisulfate. Examples of
suitable organic acid salts include, but are not limited to
acetate, cinnamate, citrate, benzoate, benzenesulfonate, fumarate,
maleate, malonate, methanesulfonate, oxalate, p-toluenesulfonate,
succinate, tartrate, trifluoromethanesulfonate and valproate.
Thus, when the compounds of the present invention represented by
the formula (I) contain an acidic group they can form an addition
salt with a suitable base. For example, such salts of the compounds
of the present invention may include their alkali metal salts such
as Li, Na, and K salts, or alkaline earth metal salts like Ca, Mg
salts, or aluminium salts, or salts with ammonia or salts of
organic bases such as lysine, and arginine.
The pharmaceutically acceptable salts of the present invention can
be synthesized from the subject compound, which contains a basic or
an acidic moiety, by conventional chemical methods. Generally the
salts are prepared by contacting the free base or acid with desired
salt-forming inorganic or organic acid or base in a suitable
solvent or dispersant or from another salt by cation or anion
exchange. Suitable solvents are, for example, ethyl acetate, ether,
alcohols, acetone, tetrahydrofuran (THF), dioxane or mixtures of
these solvents.
The present invention furthermore includes all solvates of the
compounds of the formula (I), for example hydrates, and the
solvates formed with other solvents of crystallization, such as
alcohols, ethers, ethyl acetate, dioxane, dimethylformamide (DMF),
or a lower alkyl ketone, such as acetone, or mixtures thereof.
Methods of Treatment
The compounds of formula (I) are inhibitors of PI3K and/or mTOR
and/or STAT3 and/or TNF.alpha. and/or IL-6 and find use in the
treatment of benign or malignant tumors and/or inflammation.
The present invention further provides a method of inhibiting the
tumor cell growth, tumor cell proliferation or tumorigenesis in a
mammal comprising administering to a mammal in need of such
treatment an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
Compounds of the present invention can be used to reduce, inhibit,
or diminish the proliferation of tumor cells, and thereby assist in
reducing the size of a tumor. Benign or malignant tumors that can
be treated by compounds of formula (I) include, but are not limited
to brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma,
brain tumors, glioblastoma, ependymoma, extracranial cancer,
medulloblastoma, head & neck cancer, oral cancer, thyroid
cancer, esophageal cancer, hypopharyngeal cancer, breast cancer,
lung cancer including non-small-cell lung cancer and small-cell
lung cancer, pancreatic cancer, lymphoma, melanoma, endometrial
cancer, cervical cancer, liver cancer, intrahepatic bile duct,
gastric cancer, bladder cancer, uterine cancer, colon cancer,
colorectal cancer, ovarian cancer, prostate cancer, testicular
cancer, leukemia, Ewing's sarcoma family of tumors, germ cell
tumor, Hodgkin's disease, acute lymphoblastic leukemia, acute
myeloid leukemia, adult acute myeloid leukemia, chronic myeloid
leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia,
hairy cell leukemia, human melanoma, neuroblastoma, non-Hodgkin's
lymphoma, osteosarcoma, malignant fibrous histiocytoma of bone,
retinoblastoma, rhabdomyosarcoma, soft tissue sarcomas,
supratentorial primitive neuroectodermal and pineal tumors, visual
pathway and hypothalamic glioma, Wilms' tumor, adult non-Hodgkin's
lymphoma, kidney cancer, multiple myeloma, primary central nervous
system lymphoma and skin cancer. Compounds of the formula (I) are
also of use in the treatment of inflammatory diseases, for example
psoriasis, contact dermatitis, atopic dermatitis, alopecia greata,
erythema multiforme, dermatitis herpetiformis, scleroderma,
vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid,
lupus erythematosus, pemphigus, epidermolysis bullosa acquisita,
and other inflammatory or allergic conditions of the skin.
Compounds of the present invention may also be used for the
treatment of other diseases or conditions, such as inflammatory
bowel disease, inflammation, rheumatoid arthritis, juvenile
rheumatoid arthritis, psoriatic arthritis, osteoarthritis,
refractory rheumatoid arthritis, chronic non-rheumatoid arthritis,
osteoporosis/bone resorption, Crohn's disease, septic shock,
endotoxic shock, atherosclerosis, ischemia-reperfusion injury,
coronary heart disease, vasculitis, amyloidosis, multiple
sclerosis, sepsis, chronic recurrent uveitis, hepatitis C virus
infection, malaria, ulcerative colitis, cachexia, psoriasis,
plasmocytoma, endometriosis, Behcet's disease, Wegenrer's
granulomatosis, AIDS, HIV infection, autoimmune disease, immune
deficiency, common variable immunodeficiency (CVID), chronic
graft-versus-host disease, trauma and transplant rejection, adult
respiratory distress syndrome, pulmonary fibrosis, recurrent
ovarian cancer, lymphoproliferative disease, refractory multiple
myeloma, myeloproliferative disorder, diabetes, juvenile diabetes,
meningitis, ankylosing spondylitis, skin delayed type
hypersensitivity disorders, Alzheimer's disease, systemic lupus
erythematosus and allergic asthma.
According to another aspect of the present invention, there is
provided a method for the treatment of diseases mediated by PI3K
and/or mTOR and/or STAT3, comprising administering to a mammal in
need thereof a therapeutically effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt or a
pharmaceutically acceptable solvate thereof.
According to another aspect of the present invention, the disease
mediated by PI3K and/or mTOR and/or STAT3 is cancer.
According to another aspect of the present invention, there is
provided a method for the treatment of cancer, wherein the cancer
is selected from the group comprising of brain stem glioma,
cerebellar astrocytoma, cerebral astrocytoma, brain tumors,
glioblastoma, ependymoma, extracranial cancer, medulloblastoma,
head & neck cancer, oral cancer, thyroid cancer, hypopharyngeal
cancer, breast cancer, endometrial cancer, leukemia, lung cancer
including non-small-cell lung cancer and small-cell lung cancer,
pancreatic cancer, lymphoma, melanoma, cervical cancer, liver
cancer, gastric cancer, bladder cancer, uterine cancer colon
cancer, colorectal cancer, ovarian cancer, prostate cancer,
testicular cancer, Ewing's sarcoma family of tumors, germ cell
tumor, Hodgkin's disease, acute lymphoblastic leukemia, acute
myeloid leukemia, adult acute myeloid leukemia, chronic myeloid
leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia,
hairy cell leukemia, human melanoma, neuroblastoma, non-Hodgkin's
lymphoma, osteosarcoma, malignant fibrous histiocytoma of bone,
retinoblastoma, rhabdomyosarcoma, soft tissue sarcomas,
supratentorial primitive neuroectodermal and pineal tumors, visual
pathway and hypothalamic glioma, Wilms' tumor, adult non-Hodgkin's
lymphoma, esophageal cancer, kidney cancer, multiple myeloma,
primary central nervous system lymphoma and skin cancer comprising
administering to a mammal in need thereof a therapeutically
effective amount of a compound of formula (I) or a pharmaceutically
acceptable salt or a pharmaceutically acceptable solvate
thereof.
According to another aspect of the present invention, there is
provided a method for the treatment of cancer, wherein the cancer
is selected from the group comprising of glioblastoma,
hypopharyngeal cancer, lung cancer, including non-small-cell lung
cancer and small-cell lung cancer, breast cancer, pancreatic
cancer, colon cancer, cervical cancer, prostate cancer, ovarian
cancer, multiple myeloma and human melanoma comprising
administering to a mammal in need thereof a therapeutically
effective amount of a compound of formula (I) or a pharmaceutically
acceptable salt or a pharmaceutically acceptable solvate
thereof.
According to further aspect of the present invention, there is
provided a method for the treatment of diseases mediated by
TNF-.alpha. and/or IL-6, comprising administering to a mammal in
need thereof a therapeutically effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt or a
pharmaceutically acceptable solvate thereof.
According to another aspect of the present invention, there is
provided a method for the treatment of diseases mediated by
TNF-.alpha. and/or IL-6 selected from the group comprising of
psoriasis, contact dermatitis, atopic dermatitis, alopecia greata,
erythema multiforme, dermatitis herpetiformis, scleroderma,
vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid,
lupus erythematosus, pemphigus, epidermolysis bullosa acquisita,
inflammatory bowel disease, inflammation, rheumatoid arthritis,
chronic non-rheumatoid arthritis, osteoporosis/bone resorption,
Crohn's disease, septic shock, endotoxic shock, atherosclerosis,
ischaemia-reperfusion injury, coronary heart disease, vasculitis,
amyloidosis, multiple sclerosis, sepsis, chronic recurrent uveitis,
hepatitis C virus infection, malaria, ulcerative colitis, cachexia,
plasmocytoma, endometriosis, Behcet's disease, Wegenrer's
granulomatosis, AIDS, HIV infection, autoimmune disease, immune
deficiency, common variable immunodeficiency (CVID), chronic
graft-versus-host disease, trauma and transplant rejection, adult
respiratory distress syndrome, pulmonary fibrosis, recurrent
ovarian cancer, lymphoproliferative disease, refractory multiple
myeloma, myeloproliferative disorder, diabetes, juvenile diabetes,
meningitis, ankylosing spondylitis, skin delayed type
hypersensitivity disorders, Alzheimer's disease, systemic lupus
erythematosus and allergic asthma, comprising administering to a
mammal in need thereof a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt or a
pharmaceutically acceptable solvate thereof.
According to another aspect of the present invention, there is
provided a method for the treatment of diseases mediated by
TNF-.alpha. and/or IL-6 selected from the group comprising of
rheumatoid arthritis, Crohn's disease, ulcerative colitis, septic
shock, psoriasis and atherosclerosis, comprising administering to a
mammal in need thereof a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt or a
pharmaceutically acceptable solvate thereof.
According to another aspect of the present invention, there is
provided a method for the treatment of inflammatory diseases such
as rheumatoid arthritis, Crohn's disease, ulcerative colitis,
septic shock syndrome, psoriasis and atherosclerosis comprising
administering to a mammal in need thereof a therapeutically
effective amount of a compound of formula (I) or a pharmaceutically
acceptable salt or a pharmaceutically acceptable solvate
thereof.
According to another aspect of the present invention, there is
provided the use of a compound of formula (I) or a pharmaceutically
acceptable salt thereof containing either entity for the
manufacture of a medicament for the treatment of diseases mediated
by PI3K and/or mTOR.
According to another aspect of the present invention, there is
provided the use of a compound of formula (I) or a pharmaceutically
acceptable salt thereof containing either entity for the
manufacture of a medicament for the treatment of cancers wherein
the cancer is selected from the group comprising of brain stem
glioma, cerebellar astrocytoma, cerebral astrocytoma, brain tumors,
glioblastoma, ependymoma, extracranial cancer, medulloblastoma,
head & neck cancer, oral cancer, thyroid cancer, hypopharyngeal
cancer, breast cancer, endometrial cancer, leukemia, lung cancer
including non-small-cell lung cancer and small-cell lung cancer,
pancreatic cancer, lymphoma, melanoma, cervical cancer, liver
cancer, gastric cancer, bladder cancer, uterine cancer colon
cancer, colorectal cancer, ovarian cancer, prostate cancer,
testicular cancer, Ewing's sarcoma family of tumors, germ cell
tumor, Hodgkin's disease, acute lymphoblastic leukemia, acute
myeloid leukemia, adult acute myeloid leukemia, chronic myeloid
leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia,
hairy cell leukemia, human melanoma, neuroblastoma, non-Hodgkin's
lymphoma, osteosarcoma, malignant fibrous histiocytoma of bone,
retinoblastoma, rhabdomyosarcoma, soft tissue sarcomas,
supratentorial primitive neuroectodermal and pineal tumors, visual
pathway and hypothalamic glioma, Wilms' tumor, adult non-Hodgkin's
lymphoma, esophageal cancer, kidney cancer, multiple myeloma,
primary central nervous system lymphoma and skin cancer.
According to another aspect of the present invention, there is
provided the use of a compound of formula (I) or a pharmaceutically
acceptable salt thereof for the manufacture of a medicament
containing either entity for the treatment of cancers such as
glioblastoma, hypopharyngeal cancer, lung cancer, including
non-small-cell lung cancer and small-cell lung cancer, breast
cancer, pancreatic cancer, colon cancer, cervical cancer, prostate
cancer, ovarian cancer, multiple myeloma and human melanoma.
According to another aspect of the present invention there is
provided the use of compound of formula (I) or a pharmaceutically
acceptable salt thereof for the manufacture of a medicament
containing either entity for the treatment of diseases mediated by
TNF-.alpha. and/or IL-6.
According to another aspect of the present invention there is
provided the use of compound of formula (I) or a pharmaceutically
acceptable salt thereof for the manufacture of a medicament
containing either entity for the treatment of diseases selected
from the group comprising of psoriasis, contact dermatitis, atopic
dermatitis, alopecia greata, erythema multiforme, dermatitis
herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis,
urticaria, bullous pemphigoid, lupus erythematosus, pemphigus,
epidermolysis bullosa acquisita, inflammatory bowel disease,
inflammation, rheumatoid arthritis, chronic non-rheumatoid
arthritis, osteoporosis/bone resorption, Crohn's disease, septic
shock, endotoxic shock, atherosclerosis, ischaemia-reperfusion
injury, coronary heart disease, vasculitis, amyloidosis, multiple
sclerosis, sepsis, chronic recurrent uveitis, hepatitis C virus
infection, malaria, ulcerative colitis, cachexia, plasmocytoma,
endometriosis, Behcet's disease, Wegenrer's granulomatosis, AIDS,
HIV infection, autoimmune disease, immune deficiency, common
variable immunodeficiency (CVID), chronic graft-versus-host
disease, trauma and transplant rejection, adult respiratory
distress syndrome, pulmonary fibrosis, recurrent ovarian cancer,
lymphoproliferative disease, refractory multiple myeloma,
myeloproliferative disorder, diabetes, juvenile diabetes,
meningitis, ankylosing spondylitis, skin delayed type
hypersensitivity disorders, Alzheimer's disease, systemic lupus
erythematosus and allergic asthma.
According to another aspect of the present invention, there is
provided the use of a compound of formula (I) or a pharmaceutically
acceptable salt thereof for the manufacture of a medicament for the
treatment of cancer mediated by STAT3.
According to another aspect of the present invention, there is
provided the use of a compound of formula (I) or a pharmaceutically
acceptable salt thereof for the manufacture of a medicament
containing either entity for the treatment of inflammatory diseases
such as rheumatoid arthritis, Crohn's disease, ulcerative colitis,
septic shock syndrome, psoriasis and atherosclerosis.
According to another aspect of the present invention there are
provided methods for the manufacture of medicaments comprising
compounds of formula (I), which are useful for the treatment of
cancers such as glioblastoma, hypopharyngeal cancer, lung cancer,
including non-small-cell lung cancer and small-cell lung cancer,
breast cancer, pancreatic cancer, colon cancer, cervical cancer,
prostate cancer, ovarian cancer, multiple myeloma and human
melanoma
According to another aspect of the present invention there are
provided methods for manufacture of medicaments comprising
compounds of formula (I), which are useful for the treatment of
inflammation, including diseases such as rheumatoid arthritis,
Crohn's disease, ulcerative colitis, septic shock syndrome,
psoriasis and atherosclerosis.
Pharmaceutical Compositions and Methods
According to another aspect of the present invention there are
provided pharmaceutical compositions comprising the compound of
formula (I) as active ingredients, useful in the treatment of
cancer and inflammation.
The pharmaceutical preparations according to the invention are
prepared in a manner known per se and familiar to one skilled in
the art. Pharmaceutically acceptable inert inorganic and/or organic
carriers and/or additives can be used in addition to the compounds
of formula (I), and/or their physiologically tolerable salts. For
the production of pills, tablets, coated tablets and hard gelatin
capsules it is possible to use, for example, lactose, corn starch
or derivatives thereof, gum arabica, magnesia or glucose, etc.
Carriers for soft gelatin capsules and suppositories are, for
example, fats, waxes, natural or hardened oils, etc. Suitable
carriers for the production of solutions, for example injection
solutions, or of emulsions or syrups are, for example, water,
physiological sodium chloride solution or alcohols, for example,
ethanol, propanol or glycerol, sugar solutions, such as glucose
solutions or mannitol solutions, or a mixture of the various
solvents which have been mentioned.
The pharmaceutical preparations normally contain about 1 to 99%,
for example, about 5 to 70%, or from about 5 to about 30% by weight
of the compound of the formula (I) and/or its physiologically
tolerable salt. The amount of the active ingredient of the formula
(I) and/or its physiologically tolerable salt in the pharmaceutical
preparations normally is from about 1 to 1000 mg.
The dose of the compounds of this invention, which is to be
administered, can cover a wide range. The dose to be administered
daily is to be selected to suit the desired effect. A suitable
dosage is about 0.001 to 100 mg/kg/day of the compound of formula
(I) and/or their physiologically tolerable salt, for example, about
0.01 to 50 mg/kg/day of a compound of formula (I) or a
pharmaceutically acceptable salt of the compound. If required,
higher or lower daily doses can also be administered. Actual dosage
levels of the active ingredients in the pharmaceutical compositions
of this invention may be varied so as to obtain an amount of the
active ingredient, which is effective to achieve the desired
therapeutic response for a particular patient, composition, and
mode of administration without being toxic or resulting in
unacceptable side effects to the patient.
The pharmaceuticals can be administered orally, for example in the
form of pills, tablets, coated tablets, lozenges, capsules,
dispersible powders or granules, suspensions, emulsions, syrups or
elixirs. Administration, however, can also be carried out rectally,
for example in the form of suppositories, or parenterally, for
example intravenously, intramuscularly or subcutaneously, in the
form of injectable sterile solutions or suspensions, or topically,
for example in the form of solutions, ointments, gels, lotions or
transdermally, for example, in the form of transdermal patches, or
in other ways, for example in the form of aerosols or nasal
sprays.
The selected dosage level will depend upon a variety of factors
including the activity of the particular compound of the present
invention employed, the route of administration, the time of
administration, the rate of excretion of the particular compound
being employed, the duration of the treatment, other drugs,
compounds and/or materials used in combination with the particular
compounds employed, the age, sex, weight, condition, general health
and prior medical history of the patient being treated, and like
factors well known in the medical arts.
In addition to the active ingredient of the formula (I) and/or its
physiologically acceptable salt and carrier substances, the
pharmaceutical preparations can contain additives such as, for
example, fillers, antioxidants, dispersants, emulsifiers,
defoamers, flavors, preservatives, solubilizers or colorants. They
can also contain two or more compounds of the formula (I) and/or
their physiologically tolerable salts. Furthermore, in addition to
at least one compound of the formula (I) and/or its physiologically
tolerable salt, the pharmaceutical preparations can also contain
one or more other therapeutically or prophylactically active
ingredients.
By "pharmaceutically acceptable" it is meant the carrier, diluent,
excipients, and/or salt must be compatible with the other
ingredients of the formulation, and not deleterious to the
recipient thereof.
It is understood that modifications that do not substantially
affect the activity of the various embodiments of this invention
are included within the invention disclosed herein. Accordingly,
the following examples are intended to illustrate but not to limit
the present invention.
EXPERIMENTAL
The invention is further understood by reference to the following
examples, which are intended to be purely exemplary of the
invention. The present invention is not limited in scope by the
exemplified embodiments, which are intended as illustrations of
single aspects of the invention only. Any methods that are
functionally equivalent are within the scope of the invention.
Various modifications of the invention in addition to those
described herein will become apparent to those skilled in the art
from the foregoing description. Such modifications fall within the
scope of the appended claims.
Unless otherwise stated all temperatures are in degree Celsius.
Also, in these examples and elsewhere, abbreviations have the
following meanings:
TABLE-US-00001 List of abbreviations CO.sub.2 Carbon dioxide
CHCl.sub.3 Chloroform DCM/CH.sub.2Cl.sub.2 Dichloromethane DMEM
Dulbecco's Modified Eagle Medium DMF Dimethyl formamide DMSO
Dimethyl sulfoxide EtOAc Ethyl acetate FCS Fetal calf serum FBS
Fetal Bovine Serum g Gram HCl Hydrochloric acid Hepes
N-2-Hydroxyethylpiperazine- N'-2-ethanesulfonic acid H.sub.2
Hydrogen H.sub.2SO.sub.4 Sulphuric acid MeOH Methanol mL Milliliter
MgCl.sub.2 Magnesium chloride mmol Millimoles MTS
(3-(4,5-Dimethylthiazol-2-yl)- 5-(3-carboxymethoxyphenyl)-
2-(4-sulfonyl)-2H-tetrazolium) Na.sub.2CO.sub.3 Sodium carbonate
NaHCO.sub.3 Sodium bicarbonate NaOH Sodium hydroxide NaH Sodium
hydride Na.sub.2SO.sub.4 Sodium sulphate PBS Phosphate buffer
saline Pet ether Petroleum ether POCl.sub.3 Phosphorus oxychloride
RPMI Roswell Park Memorial Institute RT Room Temperature
(20-30.degree. C.) THF Tetrahydrofuran
Intermediate 1
6-(pyridin-3-yl) imidazo[1,2-a]pyridine-3-carbaldehyde
Step 1: 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde
Bromomalonaldehyde (5230 mg, 34.68 mmol) was added to a solution of
5-bromopyridin-2-amine in acetonitrile (5000 mg, 28.90 mmol). The
reaction mixture was refluxed for 2 hours. After completion of the
reaction, the reaction mixture was quenched with sodium bicarbonate
solution and extracted with EtOAc. The organic layer was washed
with brine and dried over sodium sulfate. The organic layer was
concentrated in vacuo and the product was purified by column
chromatography using EtOAc-petroleum ether gradient to obtain the
title compound. Yield: 53%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz):
.delta. 9.94 (s, 1H), 9.50 (s, 1H), 8.54 (s, 1H), 7.86-7.85 (m,
2H); MS (m/z): 226 (M+1).sup.+.
Step 2: 6-(pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (Compound of step 1,
4000 mg, 17.77 mmol), Pyridine-3-boronic acid (3280 mg, 26.66
mmol), dichlorobis(triphenylphosphine) palladium (II) (800 mg, 20%
mmol) and 2M aqueous Na.sub.2CO.sub.3 (14 mL) were added to DMF (50
mL) and refluxed for 2 hours. The reaction mixture was diluted with
EtOAc and washed with H.sub.2O and brine. The solvent was
evaporated to obtain oil, which was purified by column
chromatography (silica gel, 1% MeOH in CHCl.sub.3) to obtain the
title compound. Yield: 62%; .sup.1HNMR (DMSO-d.sub.6; 300 MHz):
.delta. 9.96 (s, 1H), 9.59 (s, 1H), 8.92 (s, 1H), 8.63-8.61 (d,
1H), 8.55 (s, 1H), 8.15-8.11 (d, 1H), 8.06-7.96 (m, 2H), 7.56-7.51
(M, 1H); MS: m/z 224 (M+1).sup.+.
6-(pyridin-4-yl)imidazo[1,2-a]pyridine-3-carbaldehyde was prepared
by following the procedure as described for Intermediate 1, except
that Pyridine-4-boronic acid was used in place of
Pyridine-3-boronic acid.
Intermediate 2
6-(6-fluoropyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde
The title compound was prepared by following the process as
described for Intermediate 1. 6-fluoropyridin-3-ylboronic acid
(68.88 mg, 0.488 mmol) was used instead of pyridine-3-boronic acid.
Yield: 50%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.99 (s,
1H), 9.60 (s, 1H), 8.61-8.62 (d, 1H, J=1.8 Hz), 8.58 (s, 1H),
8.34-8.37 (dd, 1H, J=3 Hz, 6 Hz), 7.99-8.04 (m, 2H), 7.35-7.38 (dd,
1H, J=3 Hz); MS: m/z 242 (M+1).sup.+.
Intermediate 3
6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde
The title compound was prepared by following the process as
described for Intermediate 1. 2-fluoropyridin-3-ylboronic acid (71
mg, 0.462 mmol) was used instead of pyridine-3-boronic acid. Yield:
45%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): 9.99 (s, 1H), 9.66 (s,
1H), 8.62 (s, 1H), 8.28-8.33 (m, 2H), 7.99-8.02 (m, 2H), 7.56 (s,
1H); MS: m/z 242 (M+1).sup.+.
Intermediate 4
6-(Quinolin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde
The title compound was prepared by following the process as
described for Intermediate 1. Quinolin-3-ylboronic acid (84.6 mg,
0.488 mmol) was used instead of pyridine-3-boronic acid. Yield:
66%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): 10.01 (s, 1H), 9.88 (s,
1H), 9.19-9.20 (d, 1H, J=2.4 Hz), 8.39 (s, 2H), 8.16-8.19 (d, 1H,
J=8.4 Hz), 7.94-7.95 (m, 2H), 7.76-7.82 (m, 1H), 7.62-7.67 (t, 1H,
J=7.8 Hz, 7.2 Hz), 7.50-7.52 (m, 1H); MS: m/z 274(M+1).sup.+.
Intermediate 5
8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde
Step 1: 6-bromo-8-methylimidazo[1,2-a]pyridine-3-carbaldehyde
The title compound was prepared by following the procedure as
described for step 1 of Intermediate 1.
5-bromo-3-methylpyridin-2-amine (500 mg, 2.673 mmol) was used
instead of 5-bromopyridin-2-amine in acetonitrile to obtain the
title compound.
Yield: 52%; .sup.1H NMR (CDCl.sub.3; 300 MHz): .delta. 9.961 (s,
1H), 9.557 (s, 1H), 8.298 (s, 1H), 7.484 (s, 1H), 2.711 (s, 3H);
MS: m/z 239 (M+1).sup.+
Step 2: 8-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridine-3-carbaldehyde
The title compound was prepared by following the process as
described for step 2 of Intermediate 1.
6-Bromo-8-methylimidazo[1,2-a]pyridine-3-carbaldehyde (150 mg,
0.630 mmol) was used instead of
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde.
Yield: 60%; .sup.1H NMR (CDCl.sub.3; 300 MHz): .delta. 10.00 (s,
1H), 9.63 (s, 1H), 8.91 (s, 1H), 8.70 (s, 1H), 8.37 (s, 1H), 7.95
(d, 1H, J=5.7 Hz), 7.62 (s, 1H), 7.46 (s, 1H), 2.79 (s, 3H); MS:
m/z 236 (M+1).sup.+.
Intermediate 6
Tert-butyl
2-(3-formylimidazo[1,2-a]pyridin-6-yl)-1H-indole-1-carboxylate
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (step 1 of
Intermediate 1, 150 mg, 0.6729 mmol),
1-(tert-butoxycarbonyl)-1H-indol-2-ylboronic acid (228 mg, 0.8742
mmol), dichlorobis(triphenylphosphine) palladium (II) (30 mg, 20%
mmol) and 2M aqueous Na.sub.2CO.sub.3 (1 mL) were added to DMF (5
mL) and refluxed for 2 h. The reaction mixture was diluted with
EtOAc and washed with water and brine. The solvent was evaporated
to obtain solid residue, which was purified by column
chromatography (silica gel, 1% methanol in chloroform) to obtain
the title compound. Yield: 51%; .sup.1H NMR (DMSO-d.sub.6; 300
MHz): .delta. 11.91 (s, 1H), 9.99 (s, 1H), 9.81 (s, 1H), 8.55 (s,
1H), 8.17 (dd, 1H, J=9.3, 1.8 Hz), 7.95 (d, 1H, J=9.3 Hz), 7.56 (d,
1H, J=7.8 Hz), 7.43 (d, 1H, J=8.4 Hz), 7.142 (t, 1H, J=7.2 Hz),
7.03 (m, 2H); MS: m/z 260 (M-1).sup.+.
Intermediate 7
7-methyl-6-(pyridin-3-yl) imidazo[1,2-a]pyridine-3-carbaldehyde
Step 1: 6-bromo-7-methylimidazo[1,2-a]pyridine-3-carbaldehyde
1402-67
Bromomalonaldehyde (5000 mg, 26.74 mmol) was added to a solution of
5-bromo-4-methylpyridin-2-amine in acetonitrile (5250 mg, 34.76
mmol). The reaction mixture was refluxed for 2 hours. After
completion of the reaction, the reaction mixture was quenched with
sodium bicarbonate solution and extracted with ethyl acetate. The
organic layer was washed with brine and dried over sodium sulfate.
The organic layer was concentrated in vacuum and the product was
purified by column chromatography using ethyl acetate-petroleum
ether gradient to obtain the title compound. Yield: 79.81%; .sup.1H
NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.90 (s, 1H), 9.52 (s, 1H),
8.51 (s, 1H), 7.94 (s, 1H), 2.50 (s, 3H); MS (m/z): 239
(M+1).sup.+.
Step 2: 7-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridine-3-carbaldehyde
6-bromo-7-methylimidazo[1,2-a]pyridine-3-carbaldehyde (Compound of
step 1, 2000 mg, 7.90 mmol), Pyridine-3-boronic acid (1170 mg, 9.49
mmol), dichlorobis (triphenylphosphine) palladium (II) (200 mg, 10%
mmol) and 2M aqueous Na.sub.2CO.sub.3 (7 mL) were added to DMF (25
mL) and refluxed for 2 hours. The reaction mixture was diluted with
ethyl acetate and washed with H.sub.2O and brine. The solvent was
evaporated to obtain crude product, which was purified by column
chromatography (silica gel, 1% methanol in chloroform) to obtain
the title compound. Yield: 62%; .sup.1H NMR (DMSO-d.sub.6; 300
MHz): .delta. 9.92 (s, 1H), 9.20 (s, 1H), 8.69-8.70 (m, 2H), 8.54
(s, 1H), 7.95-7.99 (m, 1H), 7.90 (s, 1H), 7.53-7.58 (m, 1H), 2.34
(s, 3H); MS: m/z 238 (M+1)+
Intermediate 8
6-(2,4-dimethoxypyrimidin-5-yl)
imidazo[1,2-a]pyridine-3-carbaldehyde 1402-159
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (Compound of step 1 of
Intermediate 1, 200 mg, 0.89 mmol),
2,4-dimethoxypyrimidin-5-ylboronic acid (212.57 mg, 1.15 mmol),
dichlorobis(triphenylphosphine) palladium (II) (20 mg, 10% mmol)
and 2M aqueous Na.sub.2CO.sub.3 (1 mL) were added to DMF (8 mL) and
refluxed for 3 hours. The reaction mixture was diluted with ethyl
acetate and washed with H.sub.2O and brine. The solvent was
evaporated to obtain crude product, which was purified by column
chromatography (silica gel, 1% methanol in chloroform) to obtain
the title compound. Yield: 47.43%; .sup.1H NMR (DMSO-d.sub.6; 300
MHz): .delta. 9.97 (s, 1H), 9.59 (s, 1H), 8.56-8.58 (d, 2H, J=4.5
Hz), 7.88-7.98 (m, 2H), 3.96 (s, 3H), 3.98 (s, 3H); MS: m/z 285.1
(M+1)+
Intermediate 9
5-Methyl-6-(pyridin-3-yl) imidazo[1,2-a]pyridine-3-carbaldehyde
Step 1: 6-bromo-5-methylimidazo[1,2-a]pyridine-3-carbaldehyde
Bromomalonaldehyde (464 mg, 3.07 mmol) was added to a solution of
5-bromo-6-methylpyridin-2-amine (500 mg, 2.67 mmol) in
acetonitrile. The reaction mixture was refluxed for 1 hour. After
completion of the reaction, the reaction mixture was quenched with
sodium bicarbonate solution and extracted with ethyl acetate. The
organic layer was washed with brine and dried over sodium sulfate.
The organic layer was concentrated and the product was purified by
column chromatography using up to 0.5% methanol in chloroform
gradient to obtain the title compound. Yield: 28%; .sup.1H NMR
(DMSO-d.sub.6; 300 MHz): .delta. 10.06 (s, 1H), 8.51 (s, 1H),
7.86-7.83 (d, 1H, J=9.3 Hz), 7.68 (d, 1H, J=9.3 Hz), 3.03 (s, 3H);
MS: m/z 240.1 (M+1).sup.+.
Step 2: 5-Methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridine-3-carbaldehyde
6-bromo-5-methylimidazo[1,2-a]pyridine-3-carbaldehyde (125 mg,
0.523 mmol), Pyridine-3-boronic acid (77.5 mg, 0.603 mmol),
dichlorobis(triphenylphosphine) palladium (II) (36.7 mg, 0.05 mmol)
and 2M aqueous Na.sub.2CO.sub.3 (2 ml) were dissolved in DMF (3 ml)
and refluxed for 2 hours. The reaction mixture was diluted with
ethyl acetate and washed with water and brine. The solvent was
evaporated to obtain crude product, which was purified by column
chromatography (silica gel, 0.5% methanol in chloroform) to obtain
the title compound. Yield: 40%; .sup.1H NMR (DMSO-d.sub.6; 300
MHz): 69.90(s, 1H), 8.39 (s, 1H), 7.73 (d, 1H, J=9.6 Hz), 7.56 (d,
1H, J=9.3 Hz), 3.11 (s, 3H); MS: m/z 238 (M+1).sup.+.
Intermediate 10
6-(6-methylpyridin-3-yl) imidazo[1,2-a]pyridine-3-carbaldehyde
The title compound was prepared by following the procedure as
described for Intermediate 1 using
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and
6-methylpyridin-3-ylboronic acid. Yield: 40%; .sup.1H NMR
(DMSO-d.sub.6; 300 MHz): .delta. 10.0 (s, 1H), 9.74 (s, 1H), 8.79
(d, 1H, J=1.8 Hz), 8.38 (s, 1H), 7.93-7.78 (m, 4H), 7.33 (d, 1H,
J=8.1 Hz), 2.66 (s, 3H); MS: m/z 238(M+1).sup.+.
Intermediate 11
6-(5-fluoropyridin-3-yl) imidazo[1,2-a]pyridine-3-carbaldehyde
The title compound was prepared by following the procedure as
described for Intermediate 1 using
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and
5-fluoropyridin-3-ylboronic acid. Yield: 52%; .sup.1H NMR
(DMSO-d.sub.6; 300 MHz): .delta. 10.01 (s, 1H), 9.66 (s, 1H), 8.84
(s, 1H), 8.66-8.67 (d, 1H, J=2.1 Hz), 8.59 (s, 1H), 8.18-8.21 (d,
1H, J=9 Hz), 8.08-8.11 (d, 1H, J=9.6 Hz), 8.03 (s, 1H); MS: m/z
241.6 (M+1).sup.+.
Intermediate 12
6-(6-fluoro-5-methylpyridin-3-yl)
imidazo[1,2-a]pyridine-3-carbaldehyde
The title compound was prepared by following the procedure as
described for Intermediate 1 using
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and
6-fluoro-5-methylpyridin-3-ylboronic acid. Yield: 44%; .sup.1H NMR
(DMSO-d.sub.6; 300 MHz): .delta.10.0 (s, 1H), 9.59 (s, 1H),
8.58-8.00 (m, 5H), 2.24 (s, 3H), MS: m/z 256(M+1).sup.+.
Intermediate 13
6-(6-chloropyridin-3-yl) imidazo[1,2-a]pyridine-3-carbaldehyde
The title compound was prepared by following the procedure as
described for Intermediate 1 using
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and
6-chloropyridin-3-ylboronic acid. Yield: 44%; .sup.1H NMR
(DMSO-d.sub.6; 300 MHz): .delta. 10.02 (s, 1H), 9.76 (s, 1H), 8.68
(s, 1H), 8.40 (s, 1H), 7.93 (bs, 2H), 7.79 (d, 1H, J=9 Hz), 7.52
(d, 1H, J=8.1 Hz); MS: m/z 258(M+1).sup.+.
Intermediate 14
6-(1H-pyrrol-2-yl)imidazo[1,2-a]pyridine-3-carbaldehyde
The title compound was prepared by following the procedure as
described for Intermediate 1 using
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and
1H-pyrrol-2-ylboronic acid.
Yield: 21%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 11.69 (s,
1H), 9.94 (s, 1H), 9.58 (s, 1H), 8.48 (s, 1H), 8.00-7.86 (m, 2H),
6.94 (s, 1H), 6.61 (s, 1H), 6.18 (s, 1H); MS: m/z 212 (M+1).
Intermediate 15
6-(2-methoxypyrimidin-5-yl)
imidazo[1,2-a]pyridine-3-carbaldehyde
The title compound was prepared by following the procedure as
described for Intermediate 1 using
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and
2-methoxypyrimidin-5-ylboronic acid. Yield: 55.55%; .sup.1H NMR
(DMSO-d.sub.6; 300 MHz): .delta. 10.01 (s, 1H), 9.62 (s, 1H), 9.00
(s, 2H), 8.59 (s, 1H), 8.04-8.05 (m, 2H), 3.99 (s, 3H); MS: m/z 254
(M+1).sup.+.
Intermediate 16
6-(5-(trifluoromethyl)pyridin-3-yl)
imidazo[1,2-a]pyridine-3-carbaldehyde
The title compound was prepared by following the procedure as
described for Intermediate 1 using
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and
5-(trifluoromethyl)pyridin-3-ylboronic acid. Yield: 48%; .sup.1H
NMR (DMSO-d.sub.6; 300 MHz): .delta. 10.04 (s, 1H), 9.71 (s, 1H),
9.27 (s, 1H), 9.07 (s, 1H), 8.62 (s, 2H), 8.16-8.19 (dd, 1H,
J=1.8&9.3 Hz), 8.03-8.04 (d, 1H, J=9.3 Hz); MS: m/z 292
(M+1).sup.+.
Intermediate 17
6-(pyrimidin-5-yl) imidazo[1,2-a]pyridine-3-carbaldehyde
The title compound was prepared by following the procedure as
described for Intermediate 1 using
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and
pyrimidin-5-ylboronic acid.
Yield: 50%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 10.01 (s,
1H), 9.77-9.79 (m, 1H), 9.29-9.32 (m, 1H), 9.04 (s, 2H), 8.39-8.40
(m, 1H), 7.94-7.99 (m, 1H), 7.78-7.82 (dd, 1H, J=1.8 &9.3 Hz);
MS: m/z 224 (M+1).sup.+.
Intermediate 18
6-Bromoimidazo[1,2-a]pyrimidine-3-carbaldehyde 1402-113
Bromomalonaldehyde (500 mg, 2.90 mmol) was added to a solution of
5-bromopyrimidin-2-amine (526 mg, 3.49 mmol) in acetonitrile. The
reaction mixture was refluxed for 2 hours. After completion of the
reaction, the reaction mixture was quenched with sodium bicarbonate
solution and extracted with ethyl acetate. The organic layer was
washed with brine and dried over sodium sulfate. The organic layer
was concentrated and the product was purified by column
chromatography using up to 2% methanol in chloroform gradient to
obtain the title compound. Yield: 40%; .sup.1H NMR (DMSO-d.sub.6;
300 MHz): .delta. 9.98(s, 1H), 9.75-9.76 (d, 1H, J=2.4 Hz),
8.97-8.98 (d, 1H, 2.4 Hz), 8.70 (s, 1H); MS (m/z): 226
(M+1).sup.+.
EXAMPLES
Example 1
N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)benzene-
sulfonohydrazide
To a solution of
6-(pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde (Intermediate
1, 70 mg, 0.31 mmol) in ethanol (3 mL) was added methyl hydrazine
(17 mg, 0.47 mmol) at RT. The reaction was heated at 85.degree. C.
for 3 h. Ethanol was evaporated. Pyridine (2 mL) was added to this
residue, followed by addition of benzene sulfonylchloride (83 mg,
0.47 mmol). The reaction mixture was stirred at RT overnight.
Pyridine was evaporated. Water was added to this residue and
extracted with dichloromethane. Organic layer was dried over sodium
sulfate and evaporated. The crude product was purified by column
chromatography (silica gel, 1.5% methanol in chloroform) to obtain
the title compound.
Yield: 68%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.69 (s,
1H), 8.96 (s, 1H), 8.64-8.65 (d, 1H, J=4.5 Hz), 8.27 (s, 1H),
8.12-8.15 (d, 1H, J=8.1 Hz), 7.99 (s, 1H), 7.86 (s, 2H), 7.78-7.75
(d, 2H, J=8.1 Hz), 7.57-7.62 (t, 2H, J=6.3 Hz), 7.42-7.47 (t, 2H,
J=7.8 Hz), 3.22 (s, 3H); MS: m/z 392 (M+1).sup.+.
The compounds of Examples 2-82 were prepared by following the
procedure as described for Example 1, using Intermediate 1, methyl
hydrazine and an appropriate sulfonylchloride derivative.
Example 2
N, 3-dimethyl-N'-((6-pyridin-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 47%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz,): .delta. 9.74 (s,
1H), 9.00-9.01 (d, 1H, J=3 Hz), 8.67-8.69 (dd, 1H, J=1.2, 4.8 Hz,),
8.29 (s, 1H), 8.16-8.20 (m, 1H), 8.02 (s, 1H), 7.86 (s, 2H),
7.57-7.64 (m, 3H), 7.34-7.41 (m, 2H), 3.27 (s, 3H), 2.07 (s, 3H);
MS m/z 406 (M+1).sup.+.
Example 3
N, 4-dimethyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 55%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.73 (s,
1H), 8.98-8.99 (d, 1H, J=3 Hz), 8.67-8.69 (dd, 1H, J=3, 6 Hz), 8.24
(s, 1H), 8.15-8.18 (dt, 1H, J=3.6Hz), 8.02 (s, 1H), 7.88 (s, 2H);
7.66-7.68 (d, 2H, J=6 Hz), 7.59-7.63 (m, 1H), 7.25-7.28 (d, 2H, J=9
Hz), 3.22 (s, 3H), 2.27 (s, 3H); MS m/z 407 (M+1).sup.+.
Example 4
2-Fluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl) methylene)benzenesulfonohydrazide
Yield: 62.5%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.56 (s,
1H), 8.91-8.92 (d, 1H, J=1.8 Hz), 8.68-8.67 (dd, 1H, J=1.5, 4.8
Hz), 8.34 (s, 1H), 8.08-8.12 (m, 1H), 8.03 (s, 1H), 7.81-7.86 (m,
3H), 7.60-7.64 (m, 2H), 7.37-7.44 (t, 1H, J=8.7 Hz), 7.11-7.16 (t,
1H, J=7.2 Hz), 3.39 (s, 3H); MS: m/z 410 (M+1).sup.+.
Example 5
3-Fluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)benzenesulfonohydrazide
Yield: 51%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.69 (s,
1H), 8.97-8.96 (d, 1H, J=2.1 Hz), 8.66-8.64 (d, 1H, J=4.8 Hz), 8.32
(s, 1H), 8.12-8.15 (d, 1H, J=8.1 Hz), 8.03 (s, 1H), 7.88 (s, 2H),
7.57-7.64 (m, 3H), 7.50-7.54 (m, 2H), 3.28 (s, 3H); MS: m/z 410
(M+1).sup.+.
Example 6
4-Fluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl) methylene)benzenesulfonohydrazide
Yield: 55%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.72 (s,
1H), 8.97-8.78 (d, 1H, J=2.1 Hz), 8.64-8.66 (dd, 1H, J=4.5, 9Hz),
8.31 (s, 1H), 8.13-8.16 (m, 1H), 8.03 (s, 1H), 7.88 (s, 2H),
7.83-7.86 (m, 2H), 7.56-7.61 (m, 1H), 7.30-7.36 (t, 2H, J=9 Hz),
3.22 (s, 3H); MS: m/z 410 (M+1).sup.+.
Example 7
3-Bromo-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 16%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.74 (s,
1H), 9.00-9.01 (d, 1H, J=3 Hz), 8.66-8.67 (d, 1H, J=3 Hz), 8.33 (s,
1H), 8.15-8.19 (m, 1H), 8.05 (s, 1H), 7.91-7.92 (m, 2H), 7.88-7.89
(m, 1H), 7.79-7.84 (m, 2H), 7.59-7.63 (dd, 1H, J=3.6Hz), 7.43-7.49
(t, 1H, J=8.1, 7.8 Hz), 3.29 (s, 3H); MS: m/z 470 (M+1).sup.+.
Example 8
4-Bromo-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl) methylene)benzenesulfonohydrazide
Yield: 54.4%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.70 (s,
1H), 8.98-8.99 (d, 1H, J=2.1 Hz), 8.66-8.68 (dd, 1H, J=1.2, 4.8
Hz), 8.32 (s, 1H), 8.13-8.17 (m, 1H), 8.04 (s, 1H), 7.89 (s, 2H),
7.72 (s, 4H), 7.58-7.62 (m, 1H), 3.24 (s, 3H); MS: m/z 470
(M+1).sup.+.
Example 9
2-Cyano-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl) methylene)benzenesulfonohydrazide
Yield: 61.5%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.44 (s,
1H), 8.87-8.88 (d, 1H, J=2.1 Hz), 8.67-8.68 (d, 1H, J=4.8 Hz), 8.40
(s, 1H), 8.10 (s, 1H), 8.05-8.08 (m, 3H), 7.85 (s, 2H), 7.78-7.81
(d, 1H, J=7.5 Hz), 7.65-7.70 (m, 1H), 7.58-7.62 (m, 1H), 3.42 (S,
3H); MS: m/z 417 (M+1).sup.+.
Example 10
(E)-3-cyano-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methy-
lene)benzenesulfonohydrazide
Yield: 63%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.67 (s,
1H), 8.96-8.97 (d, 1H, J=3 Hz), 8.46-8.66 (d, 1H, J=6 Hz), 8.33 (s,
1H), 8.23 (s, 1H), 8.13-8.15 (d, 1H J=8.1 Hz), 8.08-8.11 (m, 2H),
8.04-8.05 (m, 1H), 7.85-7.93 (m, 2H), 7.65-7.70 (t, 1H, J=6, 9 Hz),
7.57-7.61 (m, 1H), 3.29 (s, 3H); MS: m/z 417 (M+1).sup.+.
Example 11
4-Cyano-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl) methylene)benzenesulfonohydrazide
Yield: 58%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.68 (s,
1H), 8.96-8.97 (d, 1H, J=2.1 Hz), 8.66-8.68 (d, 1H, J=4.8 Hz), 8.35
(s, 1H), 8.14-8.17 (m, 1H), 8.05 (s, 1H), 7.95-8.01 (m, 4H), 7.90
(s, 2H), 7.58-7.62 (m, 1H), 3.27 (s, 3H); MS: m/z 417
(M+1).sup.+.
Example 12
4-Methoxy-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl) methylene)benzenesulfonohydrazide
Yield: 53%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.80 (s,
1H), 8.95 (s, 1H), 8.69-8.70 (d, 1H, J=3 Hz), 8.09-8.11 (d, 1H, J=6
Hz), 8.00 (s, 1H), 7.91 (s, 1H), 7.82-7.85 (d, 1H, 9 Hz), 7.67-7.70
(d, 1H, J=9 Hz), 7.44-7.52 (m, 1H), 7.36-7.39 (d, 1H, J=9 Hz),
7.23-7.28 (m, 2H), 7.01-7.04 (d, 1H, J=3 Hz), 3.54 (s, 3H), 3.30
(s, 3H); MS: m/z 422 (M+1).sup.+.
Example 13
2,4-Difluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 52%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.61 (s,
1H), 8.92-8.93 (d, 1H, J=2.1 Hz), 8.66-8.68 (dd, 1H, J=1.5, 4.8
Hz), 8.35 (s, 1H), 8.09-8.13 (m, 1H), 8.04 (s, 1H), 7.87-7.94 (m,
3H), 7.58-7.63 (m, 1H), 7.49-7.56 (m, 1H), 7.08-7.11 (m, 1H), 3.25
(s, 3H); MS: m/z 428 (M+1).sup.+.
Example 14
2,6-Difluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 49%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.61 (s,
1H), 8.90 (s, 1H), 8.64-8.66 (d, 1H, J=4.5 Hz), 8.38 (s, 1H), 8.08
(s, 1H), 8.05 (s, 1H), 7.87 (s, 2H), 7.67-7.71 (m, 1H), 7.54-7.58
(m, 1H), 7.19-7.25 (t, 2H, J=9.18 Hz), 3.14 (s, 3H); MS: m/z 428
(M+1).sup.+.
Example 15
3,4-difluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 42.85%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.72
(s, 1H), 9.00-9.00 (d, 1H, J=2.1 Hz), 8.68-8.70 (dd, 1H, J=1.5, 4.8
Hz), 8.37 (s, 1H), 8.16-8.20 (m, 1H), 8.08 (s, 1H), 7.87-7.93 (m,
3H), 7.68-7.71 (m, 1H), 7.59-7.65 (m, 2H), 3.30 (s, 3H); MS: m/z
428 (M+1).sup.+.
Example 16
3,5-Difluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 37%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.66 (s,
1H), 8.97-8.98 (d, 1H, J=2.1 Hz), 8.65-8.67 (d, 1H, J=4.8 Hz), 8.36
(s, 1H), 8.12-8.15 (d, 1H, J=8.1 Hz), 8.06 (s, 1H), 7.90 (s, 2H),
7.57-7.61 (m, 2H), 7.48-7.50 (d, 2H, J=4.5 Hz), 3.25 (s, 3H); MS:
m/z 428 (M+1).sup.+.
Example 17
3-Chloro-2-fluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 46%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.56 (s,
1H), 8.93-8.94 (d, 1H, J=1.8 Hz), 8.70-8.72 (dd, 1H, J=4.8, 1.5
Hz), 8.40 (s, 1H), 8.10-8.14 (m, 1H), 8.08 (s, 1H), 7.91-7.92 (d,
1H, J=1.5 Hz), 7.89-7.90 (d, 2H, J=1.2 Hz), 7.78-7.82 (m, 1H),
7.62-7.66 (m, 1H), 7.19-7.24 (dt, 1H, J=8.1, 0.6 Hz), 3.44 (s, 3H);
MS m/z 444 (M+1).sup.+.
Example 18
3-Chloro-4-fluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 57%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.00 (s,
1H), 8.67-8.69 (d, 1H, J=4.5 Hz), 8.35 (s, 1H), 8.18-8.20 (d, 1H,
J=8.1 Hz), 8.09 (s, 1H), 7.85-7.98 (m, 3H), 7.80-7.84 (m, 1H),
7.53-7.65 (m, 1H), 7.35-7.38 (d, 2H, J=9.3 Hz), 3.29 (s, 3H); MS:
m/z 444 (M+1).sup.+.
Example 19
2-Fluoro-N, 5-dimethyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 60.06%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.67
(s, 1H), 8.97-8.98 (d, 1H, J=2.1 Hz), 8.67-8.69 (dd, 1H, J=1.2, 4.8
Hz), 8.32 (s, 1H), 8.14-8.17 (m, 1H), 8.02 (s, 1H), 7.87 (s, 2H),
7.60-7.65 (m, 1H), 7.55-7.56 (d, 1H, J=1.5 Hz), 7.39-7.42 (m, 1H),
7.24-7.27 (t, 1H, J=1.8 Hz), 3.39 (s, 3H), 1.90 (s, 3H); MS: m/z
424 (M+1).sup.+.
Example 20
3-Fluoro-N, 4-dimethyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 48%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.74 (s,
1H), 9.00-9.01 (d, 1H, J=1.8 Hz), 8.68-8.70 (dd, 1H, J=4.8, 1.2
Hz), 8.34 (s, 1H), 8.16-8.20 (m, 1H), 8.06 (s, 1H), 7.91 (s, 2H),
7.62-7.64 (m, 1H), 7.56-7.60 (m, 2H), 7.45-7.52 (m, 1H), 3.28 (s,
3H), 2.21 (s, 3H); MS m/z 424 (M+1).sup.+.
Example 21
5-Fluoro-N, 2-dimethyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 61%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.53 (s,
1H), 8.89-8.90 (d, 1H, J=2.1 Hz), 8.65-8.67 (dd, 1H, J=1.2, 4.5
Hz), 8.31 (s, 1H), 8.02-8.07 (m, 2H), 7.85 (s, 2H), 7.55-7.60 (m,
2H), 7.34-7.44 (m, 2H), 3.39 (s, 3H), 3.31 (s, 3H); MS: m/z 424
(M+1).sup.+.
Example 21a
3-(3-((2-(5-fluoro-2-methylphenylsulfonyl)-2-methylhydrazono)
methyl)imidazo[1,2-a]pyridin-6-yl)pyridine 1-oxide
To an ice-cooled solution of 5-fluoro-N,
2-dimethyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)
benzenesulfonohydrazide (step 1, 18 mg, 0.043 mmol) in
CH.sub.2Cl.sub.2 was added 3-chloroperoxybenzoic acid (14.46 mg,
0.065 mmol). The reaction mixture was stirred for 3 h at RT. The
reaction mixture was then poured on to water. Organic layer was
separated, washed with saturated solution of NaHCO.sub.3 and dried
over Na.sub.2SO.sub.4. Crude compound was purified by column
chromatography (silica gel, 5% EtOAc in petroleum ether) to obtain
the title compound. Yield: 64%; .sup.1H NMR (DMSO-d.sub.6; 300
MHz,): .delta. 9.45 (s, 1H), 8.57 (s, 1H), 8.32-8.31 (m, 2H), 8.03
(s, 1H), 7.83-7.79 (m, 2H), 7.67-7.64 (dd, 1H, J=8.4 Hz, 2.4 Hz),
7.56 (m, 1H), 7.43-7.36 (m, 3H), 3.40 (s, 3H), 2.54 (s, 3H); MS:
m/z 440 (M+1).sup.+.
Example 22
4-Bromo-N, 3-dimethyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 39.7%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.78 (s,
1H), 9.03-9.04 (d, 1H, J=2.1 Hz), 8.71-8.73 (dd, 1H, J=1.2, 4.8
Hz), 8.32 (s, 1H), 8.23-8.26 (m, 1H), 8.15 (s, 1H), 8.02-8.06 (dd,
1H, J=1.5, 9.3 Hz), 7.94-7.97 (d, 1H, J=9.3 Hz), 7.73-7.74 (d, 1H,
J=2.1 Hz), 7.68-7.72 (m, 2H), 7.50-7.54 (dd, 1H, J=2.1, 8.4 Hz),
3.29 (s, 3H), 2.17 (s, 3H); MS: m/z 484 (M+1).sup.+.
Example 23
N-methyl-N'-((6-(pyridine-3-yl) imidazo[1,2-a]pyridine-3-yl)
methylene)-3,5-bis(trifluoromethyl)benzenesulfonohydrazide
Yield: 47%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.79 (s,
1H), 9.01-9.02 (d, 1H, J=2.1 Hz), 8.64-8.66 (dd, 1H, J=1.2, 4.8
Hz), 8.44 (s, 1H), 8.35 (s, 1H), 8.28 (s, 2H), 8.17-8.21 (m, 1H),
8.05 (S, 1H), 7.89-7.94 (m, 2H), 7.57-7.61 (m, 1H), 3.36 (s, 3H);
MS: m/z 528 (M+1).sup.+.
Example 24
3-Cyano-4-fluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 37%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.71 (s,
1H), 8.99-9.00 (d, 1H, J=1.5 Hz), 8.67-8.69 (dd, 1H, J=9, 4.8 Hz),
8.40-8.42 (dd, 1H, J=8.4, 2.4 Hz), 8.38 (s, 1H), 8.16-8.19 (m, 2H),
8.10 (s, 1H), 7.92-7.93 (m, 2H), 7.66-7.69 (d, 1H, J=9 Hz),
7.60-7.63 (m, 1H), 3.31 (s, 3H); MS: m/z 435 (M+1).sup.+.
Example 25
N, 2-dimethyl-5 nitro-N'-((6-pyridin-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)benzenesulfonohydrazide
Yield: 35%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.58 (s,
1H), 8.86-8.87 (d, 1H, J=3 Hz), 8.61-8.63 (dd, 1H, J=1.2, 4.8 Hz),
8.53-8.54 (d, 1H, J=3 Hz), 8.35 (s, 1H), 8.28-8.32 (m, 1H),
8.06-8.10 (m, 1H), 8.03 (s, 1H), 7.86 (s, 2H), 7.68-7.71 (d, 1H,
J=8.4 Hz), 7.58-7.56 (m, 1H), 3.41 (s, 3H), 2.66 (s, 3H); MS: m/z
451 (M+1).
Example 26
2-Bromo-4,6-difluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 17.85%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.51
(s, 1H), 8.86 (s, 1H), 8.68 (s, 1H), 8.39 (s, 1H), 8.08 (s, 1H),
8.03-8.05 (d, 1H, J=6.6 Hz), 7.88 (s, 2H), 7.72-7.73 (d, 1H, J=1.2
Hz), 7.59 (S, 1H), 7.47-7.49 (m, 1H), 3.52 (s, 3H); MS: m/z 506
(M+1).sup.+.
Example 27
N, 2,4,6-tetramethyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl) methylene)benzenesulfonohydrazide
Yield: 37%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.06 (s,
1H), 8.70-7.71 (d, 2H, J=2.7 Hz), 8.25 (s, 1H), 7.98 (s, 1H),
7.93-7.97 (m, 1H), 7.80-7.83 (d, 1H, J=9.3 Hz), 7.65-7.69 (dd, 1H,
J=1.8, 9.3 Hz), 7.56-7.60 (m, 1H), 6.87 (s, 2H), 3.36 (s, 3H), 2.43
(s, 6H), 2.16 (s, 3H); MS: m/z 434 (M+1).sup.+.
Example 28
N-methyl-1-phenyl-N'-((6-pyridin-3-yl) imidazo[1,2-a]pyridine-3-yl)
methylene)benzenesulfonohydrazide
Yield: 50%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.60 (s,
1H), 8.97-8.98 (d, 1H, J=2.1 Hz), 8.61-8.63 (dd, 1H, J=1.2, 4.5
Hz), 8.21 (s, 1H), 8.11-8.14 (m, 1H), 8.01 (s, 1H), 7.81-7.89 (m,
2H), 7.48-7.54 (m, 1H), 7.23-7.26 (m, 2H), 7.07-7.13 (m, 3H), 4.66
(s, 2H), 3.20 (s, 3H); MS: m/z 406 (M+1).sup.+.
Example 29
N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)
thiophene-2-sulfonohydrazide
Yield: 64%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.90 (s,
1H), 9.03 (s, 1H), 8.62-8.63 (d, 1H, J=4.2 Hz), 8.35 (s, 1H),
8.18-8.20 (d, 1H, J=7.8 Hz), 8.05 (s, 1H), 7.87-7.96 (m, 3H),
7.69-7.70 (d, 1H, J=3.3 Hz), 7.54-7.59 (m, 1H), 7.15-7.18 (t, 1H,
J=3.9, 8.4 Hz), 3.19 (s, 3H); MS: m/z 398 (M+1).sup.+.
Example 30
N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)
quinoline-8-sulfonohydrazide
Yield: 64%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.34 (s,
1H), 8.98-8.99 (d, 1H, J=3 Hz), 8.85 (s, 1H), 8.75-8.76 (d, 1H,
J=4.8 Hz), 8.41-8.43 (d, 1H, J=7.2 Hz), 8.16-8.19 (d, 3H, J=7.8
Hz), 8.03-8.06 (d, 1H, J=8.1 Hz), 7.90 (s, 1H), 7.77 (s, 2H),
7.60-7.73 (m, 2H), 7.27-7.32 (t, 1H, J=7.8 Hz), 3.68 (s, 3H); MS:
m/z 443 (M+1).sup.+.
Example 31
N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)
cyclohexanesulfonohydrazide
Yield: 20%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.84 (s,
1H), 8.97-8.98 (d, 1H, J=1.8 Hz), 8.61-8.63 (dd, 1H, J=1.2, 4.5
Hz), 8.26 (s, 1H), 8.14-8.17 (m, 1H), 8.05 (s, 1H), 7.88 (s, 2H),
7.52-7.56 (m, 1H), 3.38 (s, 3H), 1.98-2.02 (d, 2H, J=11.4 Hz),
1.70-1.74 (m, 2H), 1.44-1.53 (m, 3H), 1.20-1.24 (m, 3H); MS: m/z
398 (M+1).sup.+.
Example 32
3-Fluoro-N, 4-dimethyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 48%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.74 (s,
1H), 9.00-9.01 (d, 1H, J=1.8 Hz), 8.68-8.70 (dd, 1H, J=4.8, 1.2
Hz), 8.34 (s, 1H), 8.16-8.20 (m, 1H), 8.06 (s, 1H), 7.91 (s, 2H),
7.62-7.64 (m, 1H), 7.56-7.60 (m, 2H), 7.45-7.52 (m, 1H), 3.28 (s,
3H), 2.21 (s, 3H); MS: m/z 424 (M+1).sup.+.
Example 33
3-Cyano-4-fluoro-N-methyl-N'-((6-(pyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 37%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.71 (s,
1H), 8.99-9.00 (d, 1H, J=1.5 Hz), 8.67-8.69 (dd, 1H, J=9, 4.8 Hz),
8.40-8.42 (dd, 1H, J=8.4, 2.4 Hz), 8.38 (s, 1H), 8.16-8.19 (m, 2H),
8.10 (s, 1H), 7.92-7.93 (m, 2H), 7.66-7.69 (d, 1H, J=9 Hz),
7.60-7.63 (m, 1H), 3.31 (s, 3H); MS: m/z 435 (M+1).sup.+.
Example 34
(E)-2,3,4-Trifluoro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3--
yl)methylene)benzenesulfonohydrazide
Yield: 50%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.64 (s,
1H), 8.94-8.95 (d, 1H, J=1.8 Hz), 8.68-8.69 (dd, 1H, J=1.2, 4.5
Hz), 8.40 (s, 1H), 8.12-8.15 (m, 1H), 8.08 (s, 1H), 7.90 (s, 2H),
7.63-7.74 (m, 1H), 7.59-7.62 (m, 1H), 7.33-7.41 (m, 1H), 3.39 (s,
3H); MS: m/z 446 (M+1).sup.+.
Example 35
(E)-4-bromo-2,5-difluoro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyrid-
in-3-yl)methylene)benzenesulfonohydrazide
Yield: 16%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.69 (s,
1H), 8.98 (s, 1H), 8.67-8.68 (d, 1H, J=4.5 Hz), 8.39 (s, 1H),
8.08-8.15 (m, 1H), 8.05 (s, 1H), 8.00-8.03 (m, 1H), 7.88 (s, 2H),
7.71-7.75 (t, 1H, J=6, 7.2 Hz), 7.60-7.63 (m, 1H), 3.40 (s, 3H);
MS: m/z 506 (M+1).sup.+.
Example 36
(E)-2-bromo-4-fluoro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-
-yl)methylene)benzenesulfonohydrazide
Yield: 23%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.28 (s,
1H), 8.82-8.83 (d, 1H, J=2.1 Hz), 8.72-8.74 (dd, 1H, J=1.5, 4.8
Hz), 8.35 (s, 1H), 8.08-8.13 (m, 1H), 8.05 (s, 1H), 8.02-8.03 (m,
1H), 7.78-7.88 (m, 3H), 7.63-7.67 (m, 1H), 6.95-6.98 (t, 1H, J=2.7,
6.3 Hz), 3.55 (s, 3H); MS: m/z 488 (M+1).sup.+.
Example 37
(E)-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-3-(trifluoromethyl)benzenesulfonohy-
drazide
Yield: 29%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.79 (s,
1H), 9.02 (s, 1H), 8.67-8.68 (d, 1H, J=3 Hz), 8.34 (s, 1H),
8.12-8.21 (m, 2H), 8.00-8.05 (m, 3H), 7.89-7.94 (m, 2H), 7.77-7.82
(t, 1H, J=7.8 Hz), 7.59-7.63 (m, 1H), 3.31 (s, 3H); MS: m/z 460
(M+1).sup.+.
Example 38
(E)-4-bromo-2,6-dichloro-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide
Yield: 8%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.29 (s,
1H), 8.78 (s, 1H), 8.69-8.70 (d, 1H, J=4.5 Hz), 8.35 (s, 1H), 8.06
(s, 1H), 7.97-7.99 (d, 1H, J=8.1 Hz), 7.85-7.88 (m, 3H), 7.77-7.80
(m, 1H), 7.57-7.61 (m, 1H), 3.54 (s, 3H); MS: m/z 537
(M+1).sup.+.
Example 39
(E)-3-chloro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)benzenesulfonohydrazide
Yield: 48%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.73 (s,
1H), 9.04 (s, 1H), 8.68-8.69 (d, 1H, J=4.8 Hz), 8.35 (s, 1H),
8.01-8.19 (m, 1H), 8.11 (s, 1H), 7.89-7.95 (m, 2H), 7.73-7.83 (m,
3H), 7.63-7.65 (m, 2H), 3.35 (s, 3H); MS: m/z 426 (M+1).sup.+.
Example 40
(E)-2-chloro-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-4-(trifluoromethyl)benzenesulfonohy-
drazide
Yield: 32%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.28 (s,
1H), 8.81-8.82 (d, 1H, J=2.1 Hz), 8.72-8.74 (dd, 1H, J=1.2, 4.5
Hz), 8.38 (s, 1H), 8.22-8.25 (d, 1H, J=8.1 Hz), 8.12 (s, 1H),
8.02-8.06 (m, 2H), 7.82-7.88 (m, 2H), 7.62-7.67 (dd, 1H, J=4.8, 7.8
Hz), 7.47-7.50 (d, 1H, J=8.4 Hz), 3.56 (s, 3H); MS: m/z 494
(M+1).sup.+.
Example 41
(E)-2-chloro-4-fluoro-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 36%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.35 (s,
1H), 8.84-8.85 (d, 1H, J=2.1 Hz), 8.71-8.73 (dd, 1H, J=1.5, 4.8
Hz), 8.34 (s, 1H), 8.08-8.11 (m, 1H), 8.04-8.07 (m, 2H), 7.80-7.88
(m, 2H), 7.69-7.73 (dd, 1H, J=2.4, 8.7 Hz), 7.63-7.67 (m, 1H),
6.97-7.04 (m, 1H), 3.52 (s, 3H); MS: m/z 444 (M+1).sup.+.
Example 42
(E)-N, 1,2-trimethyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-1H-imidazole-4-sulfonohydrazide
Yield: 44%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 8.99 (s,
1H), 9.09 (s, 1H), 8.64-8.66 (d, 1H, J=4.5 Hz), 8.29 (s, 2H), 8.01
(s, 1H), 7.85-7.94 (m, 2H), 7.71 (s, 1H), 7.56-7.60 (dd, 1H, J=4.8,
7.8 Hz), 3.47 (s, 3H), 3.29 (s, 3H), 2.10 (s, 3H); MS m/z 410
(M+1).sup.+.
Example 43
(E)-4-chloro-N, 2,5-trimethyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 35%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.64 (s,
1H), 8.96-8.73 (d, 1H, J=2.1 Hz), 8.68-8.70 (dd, 1H, J=1.5, 4.8
Hz), 8.31 (s, 1H), 8.12-8.16 (m, 1H), 8.04 (s, 1H), 7.87-7.88 (d,
2H, J=1.2 Hz), 7.77 (s, 1H), 7.60-7.64 (m, 1H), 7.48 (s, 1H), 3.39
(s, 3H), 2.52 (s, 3H), 1.95 (s, 3H); MS: m/z 454 (M+1).sup.+.
Example 44
(E)-2,5-difluoro-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 57%; .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 9.65 (s,
1H), 8.93-8.94 (d, 1H, J=1.8 Hz), 8.72-8.74 (dd, 1H, J=1.2, 4.8
Hz), 8.02-8.03 (m, 1H), 7.99-8.00 (m, 1H), 7.95 (s, 1H), 7.82-7.85
(m, 1H), 7.64-7.68 (dd, 1H, J=1.8, 9.3 Hz), 7.58-7.63 (m, 1H),
7.50-7.55 (m, 1H), 7.11-7.19 (m, 2H), 3.51 (s, 3H); MS: m/z 428
(M+1).sup.+.
Example 45
(E)-5-fluoro-2-methoxy-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-
-3-yl)methylene)benzenesulfonohydrazide
Yield: 51%; .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 9.57 (s,
1H), 8.91 (s, 1H), 8.74-8.75 (d, 1H, J=3.6 Hz), 7.97-8.00 (d, 1H,
J=7.5 Hz), 7.92 (s, 2H), 7.81-7.84 (d, 1H, J=9 Hz), 7.54-7.70 (m,
3H), 7.10-7.16 (m, 1H), 6.87-6.91 (m, 1H), 3.86 (s, 3H), 3.56 (s,
3H); MS: m/z 440 (M+1).sup.+.
Example 46
(E)-4-Iodo-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methyl-
ene)benzenesulfonohydrazide
Yield: 25%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): 9.70 (s, 1H), 8.99
(s, 1H), 8.68 (s, 1H), 8.33 (s, 1H), 8.15 (m, 2H), 7.90 (m, 3H),
7.61 (m, 3H), 3.25 (s, 3H); MS: m/z 518 (M+1).sup.+
Example 47
(E)-2'-Fluoro-N-methyl-N'-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)met-
hylene)-5'-(trifluoromethyl)biphenyl-4-sulfonohydrazide
Yield: 53%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): 9.78 (s, 1H), 9.01
(s, 1H), 8.65 (s, 1H), 8.37 (s, 1H), 8.20 (m, 11H), 3.32 (s, 3H);
MS: m/z 554 (M+1).sup.+.
Example 48
4-Methyl-3-(1-methyl-2-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) hydrazinylsulfonyl)benzoic
acid
Yield: 13%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 12.6-13.8
(bs, 1H), 9.64 (s, 1H), 8.90 (s, 1H), 8.61-8.62 (d, 1H, J=7.5 Hz),
8.38 (s, 1H), 8.31 (s, 1H), 8.04-8.07 (d, 1H, J=4.8 Hz), 7.97-8.01
(m, 2H), 7.85 (s, 2H), 7.50-7.55 (m, 2H), 3.34 (s, 3H), 2.61 (s,
3H); MS: m/z 450 (M+1).sup.+.
Example 49
4-Methoxy-3-(1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methy-
lene)hydrazinylsulfonyl)benzamide
Yield: 14.56%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.60
(s, 1H), 8.94 (s, 1H), 8.62-8.63 (d, 1H, J=4.2 Hz), 8.44-8.45 (d,
1H, J=1.8 Hz), 8.23 (s, 1H), 8.04-8.07 (dd, 1H, J=5.7 Hz, 1.8 Hz),
7.98 (bs, 3H), 7.80-7.87 (m, 2H), 7.61-7.65 (m, 1H), 7.35 (s, 1H),
7.23-7.26 (d, 1H, J=8.7 Hz), 3.84 (s, 3H), 3.42 (s, 3H); MS: m/z
434(M+1).sup.+.
Example 50
(E)-N, 2,5-trimethyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide
Yield: 40%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.75 (s,
1H), 8.94 (s, 1H), 8.72-8.73 (d, 1H, J=3.9 Hz), 8.05-8.09 (m, 1H),
7.91-7.96 (m, 2H), 7.82-7.86 (d, 1H, J=9.3 Hz), 7.73 (s, 1H),
764-7.67 (dd, 1H, J=1.8 & 9.3 Hz), 7.52-7.55 (m, 1H), 7.13-7.15
(m, 2H), 3.46 (s, 3H), 2.52 (s, 3H), 1.95 (s, 3H); MS: m/z 420
(M+1).sup.+.
Example 51
(E)-2,5-dibromo-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 25%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.60 (s,
1H), 8.95 (s, 1H), 8.73-8.74 (d, 1H, J=3.9 Hz), 8.20-8.21 (d, 1H,
J=2.4 Hz), 8.05-8.08 (m, 1H), 7.97 (s, 1H), 7.93 (s, 1H), 7.81-7.84
(d, 1H, J=9.3 Hz), 7.64-7.68 (dd, 1H, J=1.8 & 9.3 Hz),
7.55-7.70 (m, 1H), 7.51-7.54 (d, 1H, J=8.4 Hz), 7.36-7.40 (dd, 1H,
J=2.4 & 8.4 Hz), 3.65 (s, 3H); MS: m/z 549.9 (M+1).sup.+.
Example 52
(E)-2,5-dimethoxy-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 40%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.73 (s,
1H), 8.93-8.94 (d, 1H, J=1.8 Hz), 8.69-8.71 (dd, 1H, J=1.5 &
4.8 Hz), 8.04-8.08 (m, 1H), 7.88-7.92 (m, 2H), 7.77-7.80 (d, 1H,
J=9.6 Hz), 7.60-7.64 (dd, 1H, J=1.8 & 9.3 Hz), 7.53-7.57 (m,
1H), 7.43-7.44 (d, 1H, J=3 Hz), 6.93-6.97 (dd, 1H, J=3 & 9 Hz),
6.85-6.88 (d, 1H, J=9 Hz), 3.83 (s, 3H), 3.55 (s, 3H), 3.37 (s,
3H); MS: m/z 452.1 (M+1).sup.+.
Example 53
(E)-N, 2-dimethyl-N'-((6-(pyridin-3-yl) imidazo[1,2-a]pyridin-3-yl)
methylene)benzenesulfonohydrazide
Yield: 42%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.46 (s,
1H), 8.84-8.85 (d, 1H, J=1.8 Hz), 8.74-8.76 (dd, 1H, J=1.5 &
4.8 Hz), 7.90-8.00 (m, 4H), 7.77-7.80 (m, 1H), 7.50-7.59 (m, 2H),
7.31-7.37 (m, 1H), 7.22-7.26 (m, 1H), 6.87-6.92 (m, 1H), 3.49 (s,
3H), 1.65 (s, 3H); MS: m/z 406 (M+1).sup.+.
Example 54
(E)-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-2-(trifluoromethoxy)benzenesulfonoh-
ydrazide
Yield: 42%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.38 (s,
1H), 8.84-8.85 (d, 1H, J=1.8 Hz), 8.76-8.78 (m, 1H), 8.06-8.09 (dd,
1H, J=1.5 & 8.1 Hz), 7.97-8.00 (m, 1H), 7.95 (s, 1H), 7.92 (s,
1H), 7.78-7.81 (d, 1H, J=9.3 Hz), 7.47-7.58 (m, 3H), 7.32-7.35 (m,
1H), 6.98-7.03 (m, 1H), 3.57 (s, 3H); MS: m/z 476 (M+1).sup.+.
Example 55
(E)-5-chloro-2-methoxy-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 19.90%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.65
(s, 1H), 8.95-8.96 (d, 1H, J=2.1 Hz), 8.72-8.74 (m, 1H), 8.04-8.08
(m, 1H, J=9.3 Hz), 7.89-7.91 (m, 3H), 7.87-7.88 (m, 1H), 7.78-7.81
(d, 1H, J=9.3 Hz), 7.63-7.66 (dd, 1H, J=1.8 & 9.3 Hz),
7.56-7.60 (m, 1H), 7.34-7.37 (dd, 1H, J=2.7 & 9 Hz), 3.87 (s,
3H), 3.55 (s, 3H); MS: m/z 456 (M+1).sup.+.
Example 56
(E)-4-bromo-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-2-(trifluoromethoxy)benzenesulfonoh-
ydrazide
Yield: 36%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.39 (s,
1H), 8.87-8.88 (d, 1H, J=2.1 Hz), 8.78-8.80 (dd, 1H, J=1.2 &
4.5 Hz), 7.92-7.99 (m, 4H), 7.80-7.83 (d, 1H, J=9 Hz), 7.53-7.61
(m, 2H), 7.47 (s, 1H), 7.14-7.17 (dd, 1H, J=1.5 & 8.4 Hz), 3.56
(s, 3H); MS: m/z 554 (M+1).sup.+.
Example 57
(E)-2-bromo-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-5-(trifluoromethyl)benzenesulfonohy-
drazide
Yield: 25%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.62 (s,
1H), 8.92-8.93 (d, 1H, J=2.1 Hz), 8.72-8.74 (dd, 1H, J=1.5 &
4.8 Hz), 8.32-8.33 (d, 1H, J=1.8 Hz), 8.02-8.06 (m, 1H), 8.00 (s,
1H), 7.93 (s, 1H), 7.80-7.85 (m, 2H), 7.64-7.68 (dd, 1H, J=1.8
& 9.3 Hz), 7.50-7.55 (m, 2H), 3.66 (s, 3H); MS: m/z 538
(M+1).sup.+.
Example 58
(E)-N-methyl-2-nitro-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide
Yield: 50%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.52 (s,
1H), 8.88-8.89 (d, 1H, J=2.1 Hz), 8.77-8.79 (dd, 1H, J=1.5 &
4.8 Hz), 8.12-8.15 (m, 1H), 8.02-8.06 (m, 1H), 8.01 (s, 1H), 7.97
(s, 1H), 7.83-7.86 (d, 1H, J=9.3 Hz), 7.63-7.68 (m, 2H), 7.60-7.61
(d, 1H, J=1.8 Hz), 7.54-7.58 (dd, 1H, J=5.1&8.1 Hz), 7.30-7.33
(m, 1H), 3.55 (s, 3H); MS: m/z 437 (M+1).sup.+.
Example 59
(E)-N-methyl-2-(methylsulfonyl)-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 43%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.42 (s,
1H), 8.91-8.92 (d, 1H, J=1.8 Hz), 8.80-8.81 (m, 1H), 8.29-8.33 (m,
2H), 8.02-8.05 (m, 1H), 7.92 (s, 2H), 7.80-7.83 (d, 1H, J=9 Hz),
7.55-7.67 (m, 3H), 7.13-7.16 (m, 1H), 3.58 (s, 3H), 3.42 (s, 3H);
MS: m/z 470 (M+1).sup.+.
Example 60
(E)-N-methyl-2-phenoxy-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide
Yield: 46.94%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.56
(s, 1H), 8.86 (s, 1H), 8.85 (s, 1H), 7.58-7.89 (m, 2H), 7.89 (s,
2H), 7.76-7.79 (d, 1H, J=9.3 Hz), 7.55-7.59 (m, 2H), 7.24-7.28 (m,
3H), 7.12 (s, 1H), 6.87-6.89 (d, 2H, J=7.8 Hz), 6.76-6.83 (m, 2H),
3.50 (s, 3H); MS: m/z 484 (M+1).sup.+.
Example 61
(E)-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) hexane-1-sulfonohydrazide
Yield: 51%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.89 (s,
1H), 8.96-8.97 (d, 1H, J=2.4 Hz), 8.67-8.69 (dd, 1H, J=1.2&4.5
Hz), 8.03-8.07 (m, 2H), 7.97 (s, 1H), 7.85-7.88 (d, 1H, J=9.3 Hz),
7.69-7.73 (dd, 1H, J=1.8&9.3 Hz), 7.44-7.49 (dd, 1H,
J=4.8&8.1 Hz), 3.44 (s, 3H), 3.19-3.24 (m, 2H), 1.77-1.87 (m,
2H), 1.32-1.39 (m, 2H), 1.18-1.27 (m, 4H), 0.80-0.84 (m, 2H); MS:
m/z 400 (M+1).sup.+.
Example 62
(E)-N-methyl-2-morpholino-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-5-(trifluoromethyl)benzenesulfonohy-
drazide
Yield: 33%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.69 (s,
1H), 9.01-9.02 (d, 1H, J=2.1 Hz), 8.65-8.68 (dd, 1H, J=3.3&4.8
Hz), 8.11-8.22 (m, 2H), 7.92-8.02 (m, 2H), 7.85-7.91 (m, 3H),
7.57-7.67 (m, 2H), 3.79 (s, 4H), 3.56 (s, 3H), 3.02 (s, 4H); MS:
m/z 545 (M+1).sup.+.
Example 63
(E)-N,2-dimethyl-5-(methylsulfonyl)-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 52.58%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.74
(s, 1H), 8.98-8.99 (d, 1H, J=2.1 Hz), 8.66-8.67 (m, 1H), 8.31-8.36
(m, 2H), 8.15-8.17 (dd, 1H, J=1.5 &5.7 Hz), 8.07 (s, 2H),
7.88-7.97 (m, 2H), 7.69-7.72 (d, 1H, J=8.1 Hz), 7.58-7.63 (dd, 1H,
J=4.8 &7.8 Hz), 3.13 (s, 3H), 2.67 (s, 3H), 2.50 (s, 3H); MS:
m/z 484 (M+1).sup.+.
Example 64
(E)-2-bromo-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 47%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.31 (s,
1H), 8.76-8.86 (m, 2H), 8.16-8.19 (dd, 1H, J=1.5 &7.8 Hz),
7.91-7.97 (m, 3H), 7.78-7.81 (d, 1H, J=9.3 Hz), 7.61-7.65 (dd, 1H,
J=7.5& 8.1 Hz), 7.52-7.56 (m, 2H), 7.30 (s, 1H), 6.93-6.98 (m,
1H), 3.64 (s, 3H); MS: m/z 471 (M+1).sup.+.
Example 65
(E)-2-chloro-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-5-(trifluoromethyl)benzenesulfonohy-
drazide
Yield: 39%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.62 (s,
1H), 8.96 (s, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 8.14 (m, 2H), 8.03
(s, 1H), 7.88-7.95 (m, 4H), 7.59 (s, 1H), 3.56 (s, 3H); MS: m/z 494
(M+1).sup.+.
Example 66
(E)-N-methyl-6-morpholino-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)
pyridine-3-sulfonohydrazide
Yield: 45%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.86 (s,
1H), 8.96 (s, 1H), 8.70 (s, 1H), 8.57 (s, 1H), 8.07-8.10 (m, 2H),
7.94 (s, 1H), 7.68-7.87 (m, 3H), 7.51 (s, 1H), 6.46-6.49 (d, 1H,
J=8.4 Hz), 3.75 (s, 4H), 3.59 (s, 4H), 3.28 (s, 3H); MS: m/z 478
(M+1).sup.+.
Example 67
(E)-Methyl 1-methyl-5-(1-methyl-2-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)
hydrazinylsulfonyl)-1H-pyrrole-2-carboxylate
Yield: 39%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.91 (s,
1H), 8.96 (s, 1H), 8.68-8.69 (d, 1H, J=3 Hz), 8.09-8.10 (d, 1H,
J=4.5 Hz), 8.06 (s, 1H), 7.93 (s, 1H), 7.83-7.85 (d, 1H, J=5.7 Hz),
7.68-7.70 (d, 1H, J=5.7 Hz), 7.48-7.50 (dd, 1H, J=2.7&4.2 Hz),
7.15 (s, 1H), 7.05 (s, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.28 (s,
3H); MS: m/z 453 (M+1).sup.+.
Example 68
(E)-N,4-dimethyl-N'-((6-(pyridin-3-yl) imidazo[1,2-a]pyridin-3-yl)
methylene)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-sulfonohydrazide
Yield: 44%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.84 (s,
1H), 9.03 (s, 1H), 8.67 (d, 1H), 8.30 (d, 1H), 8.19-8.21 (d, 1H,
J=6.9 Hz), 8.05 (s, 2H), 7.92 (s, 2H), 7.61 (s, 1H), 7.08 (s, 1H),
4.10 (s, 2H), 3.47 (s, 3H), 3.22 (s, 3H), 3.02 (s, 2H); MS: m/z 464
(M+1).sup.+.
Example 69
(E)-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)
pyridine-3-sulfonohydrazide
Yield: 44%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.78 (s,
1H), 9.05 (s, 1H), 8.96 (s, 1H), 8.73-8.77 (m, 2H), 8.06-8.10 (m,
3H), 7.97 (s, 1H), 7.69-7.88 (m, 2H), 7.36-7.52 (m, 2H), 3.34 (s,
3H); MS: m/z 393 (M+1).sup.+.
Example 70
(E)-N-methyl-4-phenoxy-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl) methylene)benzenesulfonohydrazide
Yield: 40%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.87 (s,
1H), 8.96 (s, 1H), 8.67 (s, 1H), 8.03-8.08 (m, 2H), 7.93 (s, 1H),
7.83-7.86 (d, 1H, J=9 Hz), 7.67-7.67-7.76 (m, 3H), 7.36-7.45 (m,
3H), 7.28 (m, 1H), 6.99-7.01 (d, 2H, J=7.2 Hz), 6.85-6.88 (d, 2H,
J=8.1 Hz), 3.31 (s, 3H); MS: m/z 484 (M+1).sup.+.
Example 71
(E)-Methyl
3-(1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene) hydrazinylsulfonyl)thiophene-2-carboxylate
Yield: 48%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.53 (s,
1H), 8.89 (s, 1H), 8.68 (s, 1H), 8.34 (s, 1H), 8.06 (s, 2H), 7.87
(s, 2H), 7.75-7.77 (d, 1H, J=4.5 Hz), 7.61 (s, 1H), 7.40-7.42 (d,
1H, J=4.5 Hz), 3.80 (s, 3H), 3.49 (s, 3H); MS: m/z 456
(M+1).sup.+.
Example 72
(E)-N-methyl-N'-((6-(pyridin-3-yl) imidazo[1,2-a]pyridin-3-yl)
methylene)biphenyl-4-sulfonohydrazide
Yield: 46%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.77 (s,
1H), 9.01-9.02 (d, 1H, J=2.1 Hz), 8.65-8.67 (dd, 1H, J=1.5 &4.8
Hz), 8.33 (s, 1H), 8.17 (s, 1H), 8.04 (s, 2H), 7.89 (s, 2H), 7.86
(s, 1H), 7.76-7.78 (d, 1H, J=8.4 Hz), 7.72 (s, 1H), 7.59-7.64 (m,
3H), 7.41-7.45 (m, 3H), 3.29 (s, 3H); MS: m/z 468 (M+1).sup.+.
Example 73
(E)-Methyl 5-(1-methyl-2-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) hydrazinylsulfonyl)
furan-2-carboxylate
Yield: 32%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.82 (s,
1H), 8.96 (s, 1H), 8.68-8.69 (d, 1H, J=3.9 Hz), 8.08-8.11 (m, 2H),
7.95 (s, 1H), 7.82-7.85 (d, 1H, J=9.3 Hz), 7.68-7.72 (dd, 1H, J=1.8
&9.3 Hz), 7.45-7.49 (dd, 1H, J=5.1& 7.8 Hz), 7.07-7.12 (m,
2H), 3.72 (s, 3H), 3.48 (s, 3H); MS m/z 440 (M+1).sup.+.
Example 74
(E)-4-chloro-N-methyl-3-nitro-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 34%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.72 (s,
1H), 8.98-8.99 (d, 1H, J=2.1 Hz), 8.64-8.66 (dd, 1H, J=1.5 &4.8
Hz), 8.42-8.43 (d, 1H, J=2.1 Hz), 8.37 (s, 1H), 8.14-8.17 (m, 1H),
8.03-8.07 (m, 2H), 7.90-7.94 (m, 3H), 7.55-7.60 (dd, 1H, J=4.8
&7.8 Hz), 3.29 (s, 3H); MS: m/z 471 (M+1).sup.+.
Example 75
(E)-5-bromo-2-methoxy-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 47.5%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.68 (s,
1H), 8.95 (s, 1H), 8.72-8.95 (m, 1H), 8.06-8.10 (m, 1H), 7.97-7.98
(d, 1H, J=2.4 Hz), 7.88-7.89 (d, 2H, J=3.9 Hz), 7.78-7.81 (d, 1H,
J=9.6 Hz), 7.63-7.67 (dd, 1H, J=1.8, 9.3 Hz), 7.56-7.60 (m, 1H),
7.46-7.49 (dd, 1H, J=2.4, 8.7 Hz), 6.79-6.82 (d, 1H, J=8.7 Hz),
3.85 (s, 3H), 3.53 (s, 3H); MS: m/z 500 (M+1).sup.+.
Example 76
(E)-3-chloro-N, 2-dimethyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 45%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.38 (s,
1H), 8.84 (s, 1H), 8.5 (s, 1H), 7.91-7.95 (m, 4H), 7.78-7.81 (d,
1H, J=9.3 Hz), 7.42-7.58 (m, 3H), 6.77-6.82 (m, 1H), 3.49 (s, 3H),
2.59 (s, 3H); MS: m/z 439 (M+1).sup.+.
Example 77
(E)-5-chloro-2-fluoro-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 38%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.68 (s,
1H), 8.95 (s, 1H), 8.72-8.95 (m, 1H), 8.06-8.10 (m, 1H), 7.97-7.98
(d, 1H, J=2.4 Hz), 7.88-7.89 (d, 2H, J=3.9 Hz), 7.78-7.81 (d, 1H,
J=9.6 Hz), 7.63-7.67 (dd, 1H, J=1.8, 9.3 Hz), 7.56-7.60 (m, 1H),
7.46-7.49 (dd, 1H, J=2.4, 8.7 Hz), 6.79-6.82 (d, 1H, J=8.7 Hz),
3.53 (s, 3H); MS m/z 443 (M+1).sup.+.
Example 78
(E)-4-Fluoro-N, 2-dimethyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 48%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.45 (s,
1H), 8.88 (s, 1H), 8.77 (s, 1H), 7.80-8.05 (m, 4H), 7.81-7.84 (d,
1H, J=9.3 Hz), 7.51-7.61 (m, 2H), 6.92-6.96 (dd, 1H, J=2.4& 9
Hz), 6.55-6.61 (m, 1H), 3.52 (s, 3H), 2.55 (s, 3H); MS: m/z 423
(M+1).sup.+.
Example 79
(E)-2-methoxy-N, 6-dimethyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide
Yield: 51%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.72 (s,
1H), 8.96-8.97 (d, 1H, J=1.8 Hz), 8.72-8.74 (dd, 1H, J=1.2&4.5
Hz), 8.10-8.14 (m, 1H), 7.78-7.88 (m, 3H), 7.64-7.70 (dd, 2H,
J=2.1&16.8 Hz), 7.55-7.61 (m, 1H), 7.16-7.19 (dd, 1H,
J=1.8&8.4 Hz), 6.79-6.82 (d, 1H, J=8.4 Hz), 3.84 (s, 3H), 3.55
(s, 3H), 1.81 (s, 3H); MS: m/z 435 (M+1).sup.+.
Example 80
(E)-4-Bromo-2-chloro-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 31%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.38 (s,
1H), 8.79-8.87 (m, 2H), 7.86-8.02 (m, 5H), 7.54-7.63 (m, 3H),
7.07-7.11 (dd, 1H, J=1.8 & 8.4 Hz), 3.61 (s, 3H); MS: m/z 506
(M+1).sup.+.
Example 81
(E)-2-chloro-N-methyl-N'-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 46%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.39 (s,
1H), 8.34 (s, 1H), 8.78-8.79 (d, 1H, J=3.9 Hz), 8.14-8.17 (dd, 1H,
J=1.2&7.8 Hz), 7.97-8.01 (m, 1H), 7.94 (s, 2H), 7.83-7.86 (d,
1H, J=9.3 Hz), 7.54-7.61 (m, 2H), 7.43-7.46 (dd, 1H, J=1.2&8.1
Hz), 7.35-7.40 (m, 1H), 6.99 (s, 1H), 3.63 (s, 3H); MS: m/z 426
(M+1).sup.+.
Example 82
(E)-N-(4-(1-methyl-2-((6-(pyridin-3-yl) imidazo[1,2-a]pyridin-3-yl)
methylene)hydrazinylsulfonyl)phenyl)acetamide
Yield: 48%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 10.31 (s,
1H), 9.75 (s, 1H), 9.00-9.01 (d, 1H, J=2.1 Hz), 8.67-8.69 (dd, 1H,
J=1.5&4.8 Hz), 8.28 (s, 1H), 8.15 (s, 1H), 8.03 (s, 1H),
7.88-7.90 (m, 2H), 7.74 (s, 1H), 7.71 (s, 1H), 7.60-7.65 (m, 3H),
3.24 (s, 3H), 2.02 (s, 3H); MS: m/z 447 (M+1).sup.+.
Example 83
N'-((6-(6-fluoropyridine-3-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)-n,
2-dimethyl-5-nitrobenzenesulfonohydrazide
The title compound was prepared by following the procedure as
described for example 1, using Intermediate 2, methyl hydrazine and
2-methyl-5-nitrobenzene-1-sulfonyl chloride.
Yield: 25%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.47 (s,
1H), 8.51-8.54 (d, 2H, J=9 Hz), 8.25-8.34 (m, 3H), 7.99-8.03 (d,
1H, J=9 Hz), 7.68-7.88 (m, 3H), 7.36-7.40 (dd, 1H, J=2.1, 8.4 Hz),
3.43 (s, 3H), 2.65 (s, 3H); MS: m/z 469 (M+1).sup.+.
Example 84
(E)-N-ethyl-2-methyl-5-nitro-N'-((6-(pyridin-3-ypimidazo[1,2-a]pyridin-3-y-
l)methylene)benzenesulfonohydrazide
To a solution of
6-(pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde (Intermediate
1, 100 mg, 0.444 mmol) in ethanol (10 mL) was added ethyl hydrazine
oxalate (120 mg, 0.7998 mmol) at RT. The reaction was heated at
80.degree. C. for 4 h. EtOH was evaporated. Pyridine (5 mL) was
added to this residue, followed by addition of 2-methyl-5-nitro
benzene sulfonylchloride (126 mg, 0.533 mmol). The reaction mixture
was stirred at RT overnight. Pyridine was evaporated. Water was
added to this residue and extracted with dichloromethane. Organic
layer was dried over sodium sulphate and evaporated.The crude
product was purified by column chromatography (silica gel, 1.5%
methanol in chloroform) to obtain the title compound. Yield: 15 mg
(7%); .sup.1HNMR (CDCl.sub.3; 300 MHz): .delta. 9.57 (s, 1H), 8.75
(s, 1H), 8.69 (m, 2H), 8.31 (s, 1H), 8.18 (dd, 1H, J=8.4, 2.1 Hz),
7.99 (s, 1H), 7.91 (d, 1H, J=8.1 Hz), 7.82 (d, 1H, J=9.3 Hz), 7.63
(dd, 1H, J=9, 1.5 Hz), 7.46 (t, 2H, J=8.1 Hz), 3.90 (q, 2H, J=7.2
Hz), 2.70 (s, 3H), 1.32 (t, 3H, J=6.9 Hz); MS: m/z 463
(M-1).sup.+.
The compounds of Examples 85 and 86 were prepared by following the
procedure as described for Example 1, using
6-(pyridin-4-yl)imidazo[1,2-a]pyridine-3-carbaldehyde, methyl
hydrazine and an appropriate sulfonylchloride derivative.
Example 85
N, 2-dimethyl-5-nitro-N'-((6-(pyridine-4-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 21%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 0.78 (s,
1H), 8.69-8.71 (d, 2H, J=5.7 Hz), 8.56-8.57 (d, 1H, J=2.1 Hz), 8.35
(s, 1H), 8.29-8.33 (dd, 1H, J=2.4, 8.7 Hz), 8.04 (s, 1H), 7.85-7.95
(m, 2H), 7.72-7.74 (d, 2H, J=6 Hz), 7.69 (s, 1H), 3.42 (s, 3H),
2.67 (s, 3H); MS: m/z 451 (M+1).sup.+.
Example 86
5-Fluoro-N, 2-dimethyl-N'-((6-(pyridine-4-yl)
imidazo[1,2-a]pyridine-3-yl)methylene) benzenesulfonohydrazide
Yield: 27%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.67 (s,
1H), 8.70-8.72 (d, 2H, J=6 Hz), 8.32 (s, 1H), 8.04 (s, 1H), 7.85
(s, 2H), 7.65-7.68 (m, 2H), 7.62-7.63 (d, 1H, J=2.7 Hz), 7.37-7.46
(m, 2H), 3.43 (s, 3H), 2.48 (s, 3H); MS: m/z 424 (M+1).sup.+.
The compounds of Example 87-98 were prepared by following the
procedure as described for Example 1, using Intermediate 3, methyl
hydrazine and an appropriate sulfonylchloride derivative.
Example 87
(E)-5-Fluoro-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methy-
lene)-N,2-dimethylbenzenesulfonohydrazide
Yield: 48%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.40 (s,
1H), 8.34-8.36 (d, 1H, J=4.8 Hz), 8.29 (s, 1H), 8.08-8.15 (m, 1H),
8.04 (s, 1H), 7.83-7.87 (d, 1H, J=9.6 Hz), 7.66-7.69 (d, 1H, J=9.3
Hz), 7.52-7.59 (m, 2H), 7.37-7.42 (m, 1H), 7.30-7.34 (m, 1H), 3.42
(s, 3H), 2.43 (s, 3H); MS: m/z 442 (M+1).sup.+.
Example 88
(E)-5-Fluoro-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methy-
lene)-2-methoxy-N-methylbenzenesulfonohydrazide
Yield: 54%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.32 (s,
1H), 8.38 (s, 1H), 8.26 (s, 1H), 8.09-8.12 (m, 1H), 8.04 (s, 1H),
7.79-7.87 (m, 1H), 7.67-7.70 (d, 1H, 9 Hz), 7.61 (s, 1H), 7.41 (s,
2H), 7.20 (s, 1H), 3.82 (s, 3H), 3.47 (s, 3H); MS: m/z 458
(M+1).sup.+.
Example 89
(E)-3-fluoro-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)
methylene)-N-methylbenzenesulfonohydrazide
Yield: 55%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.76 (s,
1H), 8.33-8.35 (d, 1H, J=4.8 Hz), 8.04-8.11 (m, 2H), 7.97 (s, 1H),
7.86-7.89 (d, 1H, J=9.3 Hz), 7.68-7.72 (d, 1H, J=9.3 Hz), 7.59-7.62
(d, 1H, J=7.8 Hz), 7.50-7.60 (m, 1H), 7.36-7.46 (m, 2H), 7.23-7.26
(m, 1H), 3.33 (s, 3H); MS: m/z 428 (M+1).sup.+.
Example 90
(E)-5-chloro-2-fluoro-N'-((6-(2-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-3-
-yl)methylene)-N-methylbenzenesulfonohydrazide
Yield: 36.9%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.64 (s,
1H), 8.34-8.36 (d, 1H, J=7.5 Hz), 8.09 (s, 1H), 8.01 (s, 1H), 7.96
(s, 1H), 7.77-7.85 (m, 2H), 7.72 (s, 1H), 7.43-7.49 (m, 2H),
7.09-7.13 (d, 1H, J=9.3 Hz), 3.51 (s, 3H); MS: m/z 462
(M+1).sup.+.
Example 91
(E)-5-bromo-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)
methylene)-2-methoxy-N-methylbenzenesulfonohydrazide
Yield: 53%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.60 (s,
1H), 8.34-8.36 (m, 1H), 8.09-8.13 (m, 1H), 7.90-7.92 (m, 2H),
7.77-7.80 (d, 1H, J=9.3 Hz), 7.70-7.72 (m, 1H), 7.49-7.56 (m, 3H),
6.81-6.84 (d, 1H, J=8.7 Hz), 3.88 (s, 3H), 3.55 (s, 3H); MS: m/z
518 (M+1).sup.+.
Example 92
(E)-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-2,5-dimethoxy-N-methylbenzenesulfon-
ohydrazide
Yield: 54.9%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.60 (s,
1H), 8.32-8.33 (d, 1H, J=1.5 Hz), 8.04-8.10 (m, 1H), 7.89 (s, 2H),
7.76-7.79 (m, 1H), 7.59-7.72 (m, 1H), 7.48-7.52 (m, 1H), 7.35-7.36
(d, 1H, J=3 Hz), 6.93-6.97 (dd, 1H, 3&9 Hz), 6.88-6.90 (d, 1H,
J=6.9 Hz), 3.83 (s, 3H), 3.58 (s, 3H), 3.55 (s, 3H); MS: m/z 470
(M+1).sup.+.
Example 93
(E)-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-N,
2-dimethyl-5-(methylsulfonyl)benzenesulfonohydrazide
Yield: 47%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.56 (s,
1H), 8.34 (s, 2H), 8.27-8.28 (d, 1H, J=1.8 Hz), 8.14-8.21 (m, 1H),
8.05 (s, 1H), 8.02-8.03 (d, 1H, J=2.1 Hz), 7.86-7.89 (d, 1H, J=9.3
Hz), 7.66-7.76 (m, 2H), 7.54-7.59 (m, 1H), 3.37 (s, 3H), 3.13 (s,
3H), 2.64 (s, 3H); MS: m/z 502 (M+1).sup.+.
Example 94
(E)-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-N-methylhexane-1-sulfonohydrazide
Yield: 61%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.85 (s,
1H), 8.28-8.29 (dd, 1H, J=1.5&3.6 Hz), 8.07-8.08 (d, 1H, J=1.8
Hz), 8.04 (s, 1H), 7.98 (s, 1H), 7.84-7.87 (d, 1H, J=9.3 Hz),
7.66-7.70 (m, 1H), 7.37-7.41 (m, 1H), 3.43 (s, 3H), 3.22-3.27 (m,
2H), 1.78-1.86 (m, 2H), 1.30-1.45 (m, 2H), 1.22-1.27 (m, 4H),
0.82-0.86 (m, 2H); MS: m/z 418 (M+1).sup.+.
Example 95
(E)-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-2-methoxy-N,
4-dimethylbenzenesulfonohydrazide
Yield: 52%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.40 (s,
1H), 8.39-8.41 (d, 1H, J=3.6 Hz), 8.02-8.07 (m, 1H), 7.89 (s, 1H),
7.86 (s, 1H), 7.70-7.80 (d, 1H, J=9 Hz), 7.66-7.69 (d, 1H, J=8.1
Hz), 7.48-7.52 (m, 2H), 6.69 (s, 1H), 6.24-6.26 (d, 1H, J=7.8 Hz),
3.84 (s, 3H), 3.54 (s, 3H), 2.31 (s, 3H); MS: m/z 454
(M+1).sup.+.
Example 96
(E)-2-bromo-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)
methylene)-N-methylbenzenesulfonohydrazide
Yield: 44.77%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.26
(s, 1H), 8.40-8.42 (d, 1H, J=4.2 Hz), 8.08-8.10 (d, 1H, J=7.8 Hz),
7.97-8.02 (m, 1H), 7.93 (s, 2H), 7.78-7.81 (d, 1H, J=9.3 Hz),
7.64-7.67 (d, 1H, J=7.8 Hz), 7.48-7.57 (m, 2H), 7.23-7.28 (m, 1H),
6.81-6.86 (m, 1H), 3.64 (s, 3H); MS: m/z 490 (M+1).sup.+.
Example 97
(E)-2-cyano-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)
methylene)-N-methylbenzenesulfonohydrazide
Yield: 41%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.39 (s,
1H), 8.37-8.38 (d, 1H, J=3.6 Hz), 8.09-8.12 (d, 1H, J=8.1 Hz), 8.06
(s, 1H), 7.97-8.03 (m, 2H), 7.80-7.83 (d, 2H, J=8.1 Hz), 7.56-7.64
(m, 2H), 7.39-7.49 (m, 2H), 3.60 (s, 3H); MS: m/z 435
(M+1).sup.+.
Example 98
(E)-N'-((6-(2-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-2-methoxy-N,5-dimethylbenzenesulfon-
ohydrazide
Yield: 50%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.67 (s,
1H), 8.34-8.36 (m, 1H), 8.12-8.18 (m, 1H), 7.88 (s, 2H), 7.75-7.83
(m, 1H), 7.58-7.67 (m, 2H), 7.49-7.53 (m, 1H), 7.18-7.21 (dd, 1H,
J=2.1&8.4 Hz), 6.79-6.82 (d, 1H, J=8.7 Hz), 3.86 (s, 3H), 3.54
(s, 3H), 1.87 (s, 3H); MS: m/z 454 (M+1).sup.+.
Example 99
N, 2-Dimethyl-5-nitro-N'-((6-(quinolin-3-yl)
imidazo[1,2-a]pyridine-3-yl) methylene)benzenesulfonohydrazide
The title compound was prepared by following the procedure as
described for example 1, using Intermediate 4, methyl hydrazine and
2-methyl-5-nitrobenzene-1-sulfonyl chloride.
Yield: 60%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.83 (s,
1H), 9.20-9.21 (d, 1H, J=3 Hz), 8.72-8.73 (d, 1H, J=3 Hz),
8.55-8.56 (d, 1H, J=3 Hz), 8.37 (s, 1H), 8.23-8.27 (dd, 1H, J=3, 3
Hz), 8.03-8.10 (m, 4H), 7.90-7.93 (d, 1H, J=9 Hz), 7.81 (m, 1H),
7.66-7.71 (m, 2H), 3.41 (s, 3H), 2.67 (s, 3H); MS: m/z 501
(M+1).sup.+.
Example 100
(E)-5-Fluoro-N,2-dimethyl-N'-((8-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide
To a solution of
8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde
(Intermediate 5, 80 mg, 0.337 mmol) in ethanol (10 mL) was added
methyl hydrazine (0.035 mL, 0.675 mmol) at RT. The reaction mixture
was heated at 80.degree. C. for 4 hours. Ethanol was evaporated.
Pyridine (5 mL) was added to this residue, followed by addition
2-methyl-5-fluoro benzene sulfonylchloride (105 mg, 0.506 mmol).
The reaction mixture was stirred at RT overnight. Pyridine was
evaporated. Water was added to this residue and extracted with
dichloromethane. Organic layer was dried over sodium sulfate and
evaporated.The crude product was purified by column chromatography
(silica gel, 1.5% methanol in chloroform) to obtain the title
compound. Yield: 50 mg (27%); .sup.1H NMR (CDCl.sub.3; 300 MHz):
.delta. 9.41(s, 1H), 8.59 (s, 1H), 8.71 (d, 1H, J=3.9 Hz), 7.99 (s,
1H), 7.97 (m, 1H), 7.94 (s, 1H), 7.66 (dd, 1H, J=8.4, 2.7 Hz), 7.47
(m, 1H), 7.43 (s, 1H), 7.21 (m, 1H), 7.07 (m, 1H), 3.47 (s, 3H),
2.73 (s, 3H), 2.53 (s, 3H); MS: m/z 438 (M+1).sup.+.
The compounds of Examples 101-114 were prepared by following the
procedure as described for Example 100, using Intermediate 5,
methyl hydrazine and an appropriate sulfonylchloride
derivative.
Example 101
(E)-3,5-Difluoro-N-methyl-N'-((8-methyl-6-(pyridin-3-ypimidazo[1,2-a]pyrid-
in-3-yl)methylene)benzenesulfonohydrazide
Yield: 28%; .sup.1H NMR (CDCl.sub.3, 300M Hz): 9.59 (s, 1H), 8.91
(s, 1H) 8.68 (s, 1H), 8.09 (s, 1H,), 7.99 (d, 1H, J=7.5 Hz), 7.93
(s, 1H), 7.49-7.45 (m, 2H), 7.32 (s, 2H), 7.04 (t, 1H, J=10 Hz),
3.33 (s, 3H), 2.74 (s, 3H); MS: m/z 442(M+1).sup.+.
Example 102
(E)-4-Bromo-2,6-difluoro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,-
2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide
Yield: 22% .sup.1H NMR (CDCl.sub.3, 500M Hz): -9.37 (s, 1H), 8.89
(s, 1H) 8.09 (s, 1H), 8.15 (s, 1H), 7.97 (m, 2H), 7.46 (t, 1H,
J=6.5 Hz), 7.39 (s, 1H), 7.24 (d, 1H, J=7.5 Hz), 6.72 (t, 1H, J=8.5
Hz), 3.56 (s, 3H), 2.71 (s, 3H); MS: m/z 520(M+1).sup.+.
Example 103
(E)-N,3-dimethyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)-
methylene)benzenesulfonohydrazide
Yield: 30%; .sup.1H NMR (CDCl.sub.3, 300M Hz): 9.72 (s, 1H), 8.96
(s, 1H) 8.71 (d, 1H, J=4.2 Hz), 8.11 (d, 1H, J=7.8 Hz), 8.02 (s,
1H), 7.90 (s, 1H), 7.61 (m, 4H), 7.32 (m, 2H), 3.32 (s, 3H), 2.75
(s, 3H), 2.15 (s, 3H); MS: m/z 420(M+1).sup.+.
Example 104
(E)-2-cyano-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-
-yl)methylene)benzenesulfonohydrazide
Yield: 40 mg (28%); .sup.1H NMR (CDCl.sub.3, 300M Hz): 9.19 (s,
1H), 8.76 (m, 2H), 8.17 (d, 1H, J=7.8 Hz), 8.06 (s, 1H), 7.96 (m,
2H), 7.81 (d, 1H, J=7.8 Hz), 7.62 (t, 1H, J=7.5 Hz), 7.54 (m, 3H),
3.62 (s, 3H), 2.72 (s, 3H); MS: m/z 431(M+1).sup.+.
Example 105
(E)-3-cyano-4-fluoro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]-
pyridin-3-yl)methylene)benzenesulfonohydrazide
Yield: 23%; .sup.1H NMR (CDCl.sub.3; 300M Hz): 9.56 (s, 1H), 8.92
(d, 1H, J=1.5 Hz), 8.73 (d, 1H, J=4.5 Hz), 8.13 (s, 1H), 8.08 (m,
3H), 7.97 (s, 1H), 7.51 (m, 2H), 7.28 (m, 1H), 3.335 (s, 3H), 2.770
(s, 3H); MS: m/z 449(M+1).sup.+.
Example 106
(E)-3-cyano-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-
-yl)methylene)benzenesulfonohydrazide
Yield: 27.58%; .sup.1H NMR (CDCl.sub.3; 300M Hz): 9.57 (s, 1H),
8.91 (d, 2H, J=2.1 Hz), 8.73 (dd, 1H, J=4.8 Hz, 1.5 Hz), 8.11 (s,
1H), 8.07 (m, 3H), 7.95 (s, 1H), 7.81 (d, 1H, J=7.8 Hz), 7.53 (m,
3H), 3.33 (s, 3H), 2.76 (s, 3H); MS: m/z 431(M+1).sup.+.
Example 107
(E)-4-Bromo-N,3-dimethyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyrid-
in-3-yl)methylene)benzenesulfonohydrazide
Yield: 38%; .sup.1H NMR (CDCl.sub.3; 300M Hz): 9.69 (s, 1H), 8.98
(d, 1H, J=2.1 Hz), 8.72 (d, 1H, J=4.8 Hz), 8.08 (m, 2H), 7.92 (s,
1H), 7.61 (s, 1H), 7.53 (m, 4H), 3.31 (s, 3H), 2.76 (s, 3H), 2.17
(s, 3H); MS: m/z 498 (M+1).sup.+.
Example 108
(E)-3-Methoxy-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-
-3-yl)methylene)benzenesulfonohydrazide
Yield: 31%; .sup.1H NMR (CDCl.sub.3; 300M Hz): 9.77 (s, 1H), 8.95
(d, 1H, J=2.1 Hz), 8.70 (dd, 1H, J=2.1 Hz, 1.5 Hz), 8.121 (m, 1H),
7.91 (s, 1H), 7.52 (m, 2H), 7.40 (d, 1H, J=7.8 Hz), 7.29 (m, 2H),
7.05 (dd, 1H, J=2.4 Hz, 8.4 Hz), 3.56 (s, 3H), 3.31 (s, 3H), 2.78
(s, 3H); MS: m/z 436 (M+1).sup.+.
Example 109
(E)-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)-3-nitrobenzenesulfonohydrazide
Yield: 34%; .sup.1H NMR (CDCl.sub.3; 300M Hz): 9.60 (s, 1H), 8.92
(d, 1H, J=1.8 Hz), 8.72 (dd, 1H, J=4.8 Hz, 1.2 Hz), 8.63 (d, 1H,
J=1.8 Hz), 8.39 (dd, 1H, J=8.4 Hz, 1.2 Hz), 8.16 (m, 3H), 7.951 (s,
1H), 7.62 (t, 1H, J=8.1 Hz), 7.51 (m, 2H), 3.55 (s, 3H), 2.76 (s,
3H); MS: m/z 451 (M+1).sup.+.
Example 110
(E)-3-Chloro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl)methylene)benzenesulfonohydrazide
Yield: 31%; .sup.1H NMR (CDCl.sub.3; 300M Hz): 9.63 (s, 1H), 8.94
(d, 1H, J=1.8 Hz), 8.72 (d, 1H, J=4.8 Hz), 8.08 (m, 2H), 7.93 (s,
1H), 7.77 (s, 1H), 7.71 (d, 1H, J=7.8 Hz), 7.52 (t, 3H, J=6.3 Hz),
7.33 (m, 1H), 3.32 (s, 3H), 2.76 (s, 3H); MS: m/z 440
(M+1).sup.+.
Example 111
(E)-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)-3-(trifluoromethyl)benzenesulfonohydrazide
Yield: 34%; .sup.1H NMR (CDCl.sub.3; 300M Hz): 9.64 (s, 1H), 8.93
(s, 1H), 8.70 (s, 1H), 8.08 (m, 5H), 7.79 (d, 1H, J=7.2 Hz), 7.51
(s, 3H), 3.33 (s, 3H), 2.76 (s, 3H); MS: m/z 474 (M+1).sup.+.
Example 112
(E)-2-Bromo-4,6-difluoro-N-methyl-N'-((8-methyl-6-(pyridin-3-ypimidazo[1,2-
-a]pyridin-3-yl)methylene)benzenesulfonohydrazide
Yield: 53%; .sup.1H NMR (CDCl.sub.3; 300M Hz): 9.39 (s, 1H), 8.83
(d, 1H, J=1.8 Hz), 8.71 (dd, 1H, J=4.8 Hz, 1.5 Hz), 7.99 (s, 1H),
7.96 (t, 1H, J=1.8 Hz), 7.93 (s, 1H), 7.49 (m, 1H), 7.41 (s, 1H),
7.26 (m, 1H), 6.77 (m, 1H), 3.58 (s, 3H), 2.73 (s, 3H); MS: m/z
522(M+2).sup.+.
Example 113
(E)-4-Chloro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin--
3-yl)methylene)-3-nitrobenzenesulfonohydrazide
Yield: 20.7%; .sup.1H NMR (CDCl.sub.3; 300M Hz): 9.57 (s, 1H), 8.94
(d, 1H, J=2.1 Hz), 8.72 (d, 1H, J=4.5 Hz), 8.28 (d, 1H, J=2.1 Hz),
8.13 (s, 1H), 8.03 (m, 3H), 7.58 (d, 1H, J=8.4 Hz), 7.52 (m, 2H),
3.34 (s, 3H), 2.76 (s, 3H; MS: m/z 485(M+1).sup.+.
Example 114
(E)-2-Bromo-4-fluoro-N-methyl-N'-((8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]-
pyridin-3-yl)methylene)benzenesulfonohydrazide
Yield: 45%; .sup.1H NMR (CDCl.sub.3, 300M Hz): 9.15 (s, 1H), 8.83
(d, 1H, J=1.8 Hz), 8.78 (d, 1H, J=3.9 Hz), 8.24 (m, 1H), 7.94 (d,
3H, J=9.9 Hz), 7.55 (m, 1H), 7.39 (d, 1H, J=2.4 Hz), 7.36 (s, 1H),
6.69 (m, 1H), 3.63 (s, 3H), 2.71 (s, 3H); MS: m/z
502(M+1).sup.+.
Example 115
(E)-N'-((6-(1H-indol-2-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-5-fluoro-N-
,2-dimethylbenzenesulfonohydrazide
To a solution of
6-(1H-indol-2-yl)imidazo[1,2-a]pyridine-3-carbaldehyde
(Intermediate 6, 115 mg, 0.3691 mmol) in ethanol (10 mL) was added
methyl hydrazine (0.04 mL, 0.7395 mmol) at RT. The reaction mixture
was heated at 80.degree. C. for 4 h. Ethanol was evaporated.
Pyridine (5 mL) was added to this residue, followed by addition of
2-methyl-5-fluoro benzene sulfonylchloride (0.07 mL, 0.5535 mmol).
The reaction mixture was stirred at RT overnight. Pyridine was
evaporated. Water was added to this residue and extracted with
dichloromethane. Organic layer was dried over sodium sulfate and
evaporated. The crude product was purified by column chromatography
(Silica gel, 1.5% methanol in chloroform) to obtain the title
compound. Yield: 28 mg (17%); .sup.1H NMR (DMSO-d.sub.6; 500 MHz):
.delta. 11.83 (s, 1H), 9.09 (s, 1H), 9.81 (s, 1H), 8.34 (s, 1H),
8.27 (d, 1H, J=9.5 Hz), 8.08 (d, 1H, J=9.5 Hz), 7.74 (d, 1H, J=6.5
Hz), 7.61 (d, 1H, J=8 Hz), 7.43 (m, 3H), 7.18 (t, 1H, J=8), 7.07
(t, 1H, J=7.5 Hz), 6.91 (s, 1H), 3.48 (s, 3H); MS: m/z 460
(M-1).sup.+.
Example 116
(E)-5-fluoro-N,2-dimethyl-N'-((6-(1-methyl-1H-indol-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide
To a solution of N'-((6-(1H-indol-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-5-fluoro-N,2-dimethylbenzenesulfono-
hydrazide (50 mg, 1084 mmoles) in DMF (3 ml) was added NaH (6.5 mg,
0.1626 mmoles). The solution was stirred for 15 minutes and then
methyl iodide was added to it. The reaction was quenched with
methanol. The reaction mixture was evaporated to dryness. The
residue obtained was dissolved in EtOAc washed with water and
brine. EtOAc layer was separated, dried over sodium sulfate and
evaporated. Crude material was purified by column chromatography
(100-200 mesh size silica gel, 1.0% MeOH in CHCl.sub.3). Yield: 25
mg (49%) .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta. 9.28 (s, 1H),
8.01 (s, 1H) 7.91 (s, 1H), 7.77 (d, 1H, J=9 Hz), 7.70 (d, 1H, J=7.5
Hz), 7.59 (d, 1H, J=8 Hz), 7.49 (d, 1H, J=9.5 Hz), 7.42 (d, 1H, J=8
Hz), 7.33 (t, 1H, J=7 Hz), 7.21 (t, 1H, J=6 Hz), 7.07 (m, 1H), 6.84
(m, 1H), 6.57 (s, 1H), 3.75 (s, 3H), 3.44 (s, 3H), 2.71 (s, 3H);
MS: m/z 476(M+1).sup.+
The compounds of Examples 117-124 were prepared by following the
procedure as described for Example 1, using Intermediate 7, methyl
hydrazine and an appropriate sulfonylchloride derivative.
Example 117
2-Cyano-N-methyl-N'-((7-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 24.62%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 8.83
(s, 1H), 8.75-8.77 (dd, 1H, J=4.8 Hz, 1.5 Hz), 8.60 (s, 1H), 8.40
(s, 1H), 8.02 (s, 2H), 7.88-7.92 (m, 1H), 7.81-7.84 (d, 1H, J=8.1
Hz), 7.76-7.79 (dd, 1H, J=7.5 Hz, 0.6 Hz), 7.73 (s, 1H), 7.61-7.65
(dd, 1H, J=7.8 Hz, 5.1 Hz), 7.48-7.43 (m, 1H), 3.44 (s, 3H), 2.27
(s, 3H); MS: m/z 431.1 (M+1)
Example 118
5-Fluoro-N, 2-dimethyl-N'-((7-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 38%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 8.98 (s,
1H), 8.70-8.72 (dd, 1H, J=4.8 Hz, 1.5 Hz), 8.607-8.612 (d, 1H,
J=10.5 Hz), 7.97 (s, 1H), 7.85-7.87 (m, 2H), 7.71 (s, 1H),
7.55-7.60 (dd, 1H, J=7.5 Hz, 4.8 Hz), 7.42-7.34 (m, 3H), 3.39 (s,
3H), 2.41 (s, 3H), 2.28 (s, 3H); MS: m/z 438.1(M+1).sup.+.
Example 119
N, 3-dimethyl-N'-((7-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide
Yield: 34%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.20 (s,
1H), 8.73-8.75 (m, 2H), 8.26 (s, 1H), 7.97-8.02 (m, 1H), 7.97 (s,
1H), 7.74 (s, 1H), 7.61-7.65 (dd, 1H, J=8.1 Hz, 5.1 Hz), 7.47 (s,
1H), 7.41-7.43 (m, 2H), 7.20-7.25 (t, 1H, J=7.5 Hz), 3.24 (s, 3H),
2.33 (s, 3H), 2.20 (s, 3H); MS: m/z 420.1(M+1).sup.+.
Example 120
3-Fluoro-N-methyl-N'-((7-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
Yield: 51.48%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.15
(s, 1H), 8.71-8.74 (m, 2H), 8.31 (s, 1H), 7.99 (s, 1H), 7.96-7.97
(m, 1H), 7.75 (s, 1H), 7.61-7.64 (dd, 1H, J=7.8 Hz, 2.4 Hz),
7.46-7.50 (m, 4H), 3.27 (s, 3H), 2.32 (s, 3H); MS: m/z
424.1(M+1).sup.+.
Example 121
3-Chloro-N-methyl-N'-((7-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl-
)methylene)benzenesulfonohydrazide
Yield: 40%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.18 (s,
1H), 8.72-8.74 (m, 2H), 8.30 (s, 1H), 7.98-8.01 (m, 2H), 7.76 (s,
1H), 7.70-7.72 (d, 1H, J=8.1 Hz), 7.60-7.67 (m, 3H), 7.41-7.47 (m,
1H), 3.26 (s, 3H), 2.33 (s, 3H); MS: m/z 440.1(M+1).sup.+.
Example 122
N-methyl-N'-((7-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-3-(trifluoromethyl)benzenesulfonohy-
drazide
Yield: 23%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.21 (s,
1H), 8.71-8.73 (m, 2H), 8.30 (s, 1H), 8.02-8.05 (d, 1H, J=8.1 Hz),
7.99 (s, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.47 (s, 1H), 7.76 (s,
1H), 7.66-7.72 (t, 1H, J=7.8 Hz, 7.5 Hz), 7.58-7.62 (dd, 1H, J=7.8
Hz, 4.8 Hz), 3.24 (s, 3H), 2.34 (s, 3H).
Example 123
3-Bromo-N-methyl-N'-((7-methyl-6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)benzenesulfonohydrazide
Yield: 26%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 8.79-8.80
(dd, 1H, J=4.8 Hz, 1.2 Hz), 8.72 (s, 1H), 8.56-8.57 (d, 1H, J=2.1
Hz), 8.26 (s, 1H), 7.96 (s, 1H), 7.86-7.89 (m, 1H), 7.76-7.79 (d,
1H, J=8.1 Hz), 7.72-7.75 (dd, 1H, J=7.8 Hz, 1.2 Hz), 7.69 (s, 1H),
7.64-7.67 (m, 1H), 7.36-7.41 (m, 1H), 6.81-6.86 (t, 1H, J=7.8 Hz,
7.5 Hz), 3.52 (s, 3H), 2.25 (s, 3H); MS: m/z 483.6(M+1).sup.+.
Example 124
5-Fluoro-N,
2-dimethyl-N'-((7-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methy-
lene)benzenesulfonohydrazide
Yield: 42.57%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 8.96
(s, 1H), 8.66-8.68 (dd, 1H, J=4.8 Hz, 1.5 Hz), 8.539-8.544 (d, 1H,
J=1.5 Hz), 8.440-8.448 (d, 1H, J=2.4 Hz), 8.32 (s, 1H), 8.26-8.32
(dd, 1H, J=8.4 Hz, 2.4 Hz), 7.98 (s, 1H), 7.83-7.87 (m, 1H), 7.72
(s, 1H), 7.62-7.65 (d, 1H, J=9 Hz), 7.51-7.55 (dd, 1H, J=7.8 Hz,
4.8 Hz), 2.59 (s, 3H), 2.26 (s, 3H), 2.50 (s, 3H); MS: m/z
465.1(M+1).sup.+.
Example 125
N'-((6-(2,4-dimethoxypyrimidin-5-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-5-fluoro-N,
2-dimethylbenzenesulfonohydrazide
The title compound was prepared by following the procedure as
described for example 1, using Intermediate 8, methyl hydrazine and
2-methyl-5-fluorobenzene-1-sulfonyl chloride.
Yield: 7%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.21-9.22
(d, 1H, J=0.6 Hz), 8.39 (s, 1H), 8.29 (s, 1H), 8.02 (s, 1H),
7.78-7.81 (d, 1H, J=9.6 Hz, 0.6 Hz), 7.58-7.61 (dd, 1H, J=9.3 Hz,
1.8 Hz), 7.49-7.53 (dd, 1H, J=8.7 Hz, 3 Hz), 7.41-7.43 (m, 1H),
7.34-7.39 (m, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.42 (s, 3H), 2.44
(s, 3H); MS: m/z 485.2 (M+1).sup.+.
The compounds of Examples 126 and 127 were prepared by following
the procedure as described for Example 1, using Intermediate 9,
methyl hydrazine and an appropriate sulfonylchloride
derivative.
Example 126
(E)-5-Fluoro-N,2-dimethyl-N'-((5-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyri-
din-3-yl)methylene)benzenesulfonohydrazide
Yield: 24%; .sup.1H NMR (CDCl.sub.3; 300M Hz): .delta. 8.71 (m,
1H), 8.62 (d, 1H, J=1.8 Hz), 8.34 (s, 1H), 8.01 (s, 1H), 7.75 (dd,
1H, J=8.4 Hz, 2.7 Hz), 7.68 (m, 2H), 7.47 (m, 1H), 7.33 (m, 3H),
3.37 (s, 3H), 2.64 (s, 3H), 2.63 (s, 3H); MS: m/z
438(M+1).sup.+.
Example 127
(E)-N,3-dimethyl-N'-((5-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)-
methylene)benzenesulfonohydrazide
Yield: 17%; .sup.1H NMR (CDCl.sub.3; 300 MHz): .delta. 8.71 (m,
1H), 8.64 (d, 1H, J=1.5 Hz), 8.62 (s, 1H), 8.12 (s, 1H), 7.71 (m,
5H), 7.47 (m, 3H), 7.26 (d, 1H, J=9 Hz), 3.20 (s, 3H), 2.73 (s,
3H), 2.45 (s, 3H); MS: m/z 420(M+1).sup.+.
The compounds of Examples 128-131 were prepared by following the
procedure as described for Example 1, using Intermediate 10, methyl
hydrazine and an appropriate sulfonylchloride derivative.
Example 128
(E)-5-fluoro-N,2-dimethyl-N'-((6-(6-methylpyridin-3-yl)imidazo[1,2-a]pyrid-
in-3-yl)methylene)benzenesulfonohydrazide
Yield: 38%; .sup.1H NMR (CDCl.sub.3; 300M Hz): .delta. 9.50 (s,
1H), 8.74 (s, 1H), 7.99 (s, 1H), 7.91 (s, 1H), 7.87 (dd, 1H, J=8.1
Hz, 2.4 Hz), 7.78 (d, 1H, J=9 Hz), 7.71 (dd, 1H, J=8.4 Hz, 2.7 Hz),
7.59 (dd, 1H, J=9.6 Hz, 1.8 Hz), 7.35 (d, 1H, J=8.1 Hz), 7.25 (m,
1H), 7.08 (m, 1H), 3.45 (s, 3H), 2.68 (s, 3H), 2.53 (s, 3H); MS:
m/z 438 (M+1).sup.+.
Example 129
(E)-N-methyl-N'-((6-(6-methylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methy-
lene)-2-(trifluoromethoxy)benzenesulfonohydrazide
Yield: 22%; .sup.1H NMR (CDCl.sub.3; 300M Hz): .delta. 9.36 (s,
1H), 8.72 (s, 1H), 8.10 (dd, 1H, J=7.8 Hz, 1.8 Hz), 7.94 (s, 1H),
7.90 (m, 2H), 7.79 (d, 1H, J=9 Hz), 7.57 (m, 2H), 7.41 (d, 1H,
J=7.8 Hz), 7.34 (m, 1H), 7.04 (m, 1H), 3.57 (s, 3H), 2.72 (s, 3H);
MS: m/z 490 (M+1).sup.+.
Example 130
(E)-5-Fluoro-2-methoxy-N-methyl-N'-((6-(6-methylpyridin-3-yl)imidazo[1,2-a-
]pyridin-3-yl)methylene)benzenesulfonohydrazide
Yield: 22%; .sup.1H NMR (CDCl.sub.3; 300 MHz): .delta. 9.50 (s,
1H), 8.773 (s, 1H), 7.91 (s, 1H), 7.88 (m, 2H), 7.79 (d, 1H, J=9
Hz), 7.71 (dd, 1H, J=7.8 Hz, 2.7 Hz), 7.61 (dd, 1H, J=9.3 Hz, 1.8
Hz), 7.42 (d, 1H, J=8.1 Hz), 7.13 (m, 1H), 6.90 (m, 1H), 3.85 (s,
3H), 3.55 (s, 3H), 2.69 (s, 3H); MS m/z 454(M+1).sup.+.
Example 131
(E)-N,2-dimethyl-N'-((6-(6-methylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)m-
ethylene)benzenesulfonohydrazide
Yield: 24%; .sup.1H NMR (CDCl.sub.3; 300 MHz): .delta. 9.45 (s,
1H), 8.73 (s, 1H), 8.01 (d, 1H, J=7.5 Hz), 7.95 (s, 1H), 7.89 (m,
2H), 7.79 (d, 1H, J=9.3 Hz), 7.58 (dd, 1H, J=9.3 Hz, 1.8 Hz), 7.39
(m, 2H), 7.25 (m, 1H), 6.93 (m, 1H), 3.47 (s, 3H), 2.70 (s, 3H),
2.56 (s, 3H); MS m/z 420 (M+1).sup.+.
The compounds of Examples 132 and 133 were prepared by following
the procedure as described for Example 1, using Intermediate 11,
methyl hydrazine and an appropriate sulfonylchloride
derivative.
Example 132
(E)-5-fluoro-N'-((6-(5-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)-N,
2-dimethylbenzenesulfonohydrazide
Yield: 37%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.63 (s,
1H), 8.72 (s, 1H), 8.58-8.59 (d, 1H, J=2.4 Hz), 7.86-8.00 (m, 3H),
7.59-7.70 (m, 3H), 7.28 (s, 1H), 7.09-7.12 (m, 1H), 3.48 (s, 3H),
2.55 (s, 3H); MS: m/z 441 (M+1).sup.+.
Example 133
(E)-5-Fluoro-N'-((6-(5-fluoropyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)
methylene)-2-methoxy-N-methylbenzenesulfonohydrazide
Yield: 54%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.62 (s,
1H), 8.75 (s, 1H), 8.60-8.61 (d, 1H, J=2.7 Hz), 7.91 (s, 2H),
7.68-7.83 (m, 3H), 7.58-7.61 (dd, 1H, J=1.8 & 9.3 Hz),
7.09-7.16 (m, 1H), 6.90-6.91 (m, 1H), 3.86 (s, 3H), 3.56 (s, 3H);
MS m/z 457 (M+1).sup.+.
Example 134
(E)-5-Fluoro-N'-((6-(6-fluoro-5-methylpyridin-3-yl)imidazo[1,2-a]pyridin-3-
-yl)methylene)-N,2-dimethylbenzenesulfonohydrazide
The title compound was prepared by following the procedure as
described for Example 1, using Intermediate 12 and
5-fluoro-2-methylbenzene-1-sulfonyl chloride.
Yield: 40 mg (26%); .sup.1H NMR (CDCl.sub.3; 300 MHz): .delta. 9.62
(s, 1H), 8.25 (s, 1H), 7.97 (m, 3H), 7.81 (d, 1H, J=9.6 Hz), 7.64
(m, 2H), 7.26 (m, 1H), 7.11 (m, 1H), 3.46 (s, 3H), 2.54 (s, 3H);
MS: m/z 456(M+1).sup.+.
Example 135
(E)-N'-((6-(6-Chloropyridins-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-5--
fluoro-N,2-dimethylbenzenesulfonohydrazide
The title compound was prepared by following the procedure as
described for Example 1, using Intermediate 13 and
5-fluoro-2-methylbenzene-1-sulfonyl chloride.
Yield: 26%; .sup.1H NMR (CDCl.sub.3; 300M Hz): .delta. 9.60 (s,
1H), 8.63 (s, 1H), 7.97 (m, 3H), 7.83 (d, 1H, J=9 Hz), 7.67 (m,
1H), 7.59 (t, 2H, J=10.5 Hz), 7.24 (m, 1H), 7.12 (m, 1H), 3.47 (s,
3H), 2.53 (s, 3H); MS m/z 457(M+1).sup.+.
Example 136
(E)-V-((6-(1H-Pyrrol-2-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-5-fluoro-N-
,2-dimethylbenzenesulfonohydrazide
The title compound was prepared by following the procedure as
described for Example 1, using Intermediate 14 and
5-fluoro-2-methylbenzene-1-sulfonyl chloride.
Yield: 20%; .sup.1H NMR (CDCl.sub.3, 300M Hz): .delta. 9.89 (s,
1H), 8.97 (s, 1H), 8.19 (m, 6H), 6.96 (s, 2H), 6.35 (s, 1H), 3.38
(s, 3H), 2.77 (s, 3H); MS m/z 412M+1).sup.+.
Example 137
(E)-5-fluoro-N'-((6-(6-methoxypyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)meth-
ylene)-N,2-dimethylbenzenesulfonohydrazide
The title compound was prepared by following the procedure as
described for Example 1, using
6-(6-methoxypyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde, and
5-fluoro-2-methylbenzene-1-sulfonyl chloride.
Yield: 23%; .sup.1H NMR (CDCl.sub.3; 300M Hz): 9.48 (s, 1H), 8.389
(s, 1H), 7.98 (s, 1H), 7.91 (bs, 1H), 7.85 (m, 2H), 7.73 (m, 1H),
7.59 (m, 1H), 7.25 (m, 1H), 7.11 (m, 1H), 6.96 (d, 1H, J=8.4 Hz),
4.04 (s, 3H), 3.47 (s, 3H), 2.53 (s, 3H); MS m/z
454(M+1).sup.+.
Example 138
(E)-5-Fluoro-N-((6-(2-methoxypyrimidin-5-yl)
imidazo[1,2-a]pyridine-3-yl)methylene)-N,
2-dimethylbenzenesulfonohydrazide
The title compound was prepared by following the procedure as
described for Example 1, using Intermediate 15 and
5-fluoro-2-methylbenzene-1-sulfonyl chloride.
Yield: 47%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.49 (s,
1H), 8.75 (s, 2H), 7.99 (s, 1H), 7.94 (s, 1H), 7.83-7.86 (d, 1H,
J=9.3 Hz), 7.67-7.70 (dd, 1H, J=2.7 &8.4 Hz), 7.51-7.55 (dd,
1H, J=1.8 &9.3 Hz), 7.23-7.26 (m, 1H), 7.08-7.14 (m, 1H), 4.15
(s, 3H), 3.48 (s, 3H), 2.54 (s, 3H); MS: m/z 455 (M+1).sup.+.
Example 139
(E)-5-fluoro-N, 2-dimethyl-N'-((6-(5-(trifluoromethyl)pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide
The title compound was prepared by following the procedure as
described for Example 1, using Intermediate 16 and
5-fluoro-2-methylbenzene-1-sulfonyl chloride.
Yield: 40%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.72 (s,
1H), 9.09 (s, 1H), 8.99 (s, 1H), 8.24 (s, 1H), 7.96-7.99 (d, 2H,
J=9.6 Hz), 7.85-7.88 (d, 1H, J=9 Hz), 7.59-7.65 (m, 2H), 7.21-7.23
(m, 1H), 7.06-7.09 (m, 1H), 3.48 (s, 3H), 2.54 (s, 3H); MS: m/z 513
(Na.sup.+).
Example 140
(E)-5-Fluoro-N,
2-dimethyl-N'-((6-(pyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)methylene)be-
nzenesulfonohydrazide
The title compound was prepared by following the procedure as
described for Example 1, using Intermediate 17 and
5-fluoro-2-methylbenzene-1-sulfonyl chloride.
Yield: 47.87%; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.62
(s, 1H), 9.34 (s, 1H), 9.01 (s, 2H), 8.00 (s, 1H), 7.96 (s, 1H),
7.85-7.88 (d, 1H, J=9.6 Hz), 7.64-7.67 (dd, 1H, J=2.7& 8.4 Hz),
7.56-7.60 (dd, 1H, J=1.8 & 9.3 Hz), 7.23-7.25 (m, 1H),
7.09-7.10 (m, 1H), 3.48 (s, 3H), 2.55 (s, 3H); MS: m/z 425
(M+1).sup.+.
Example 141
(E)-N-benzyl-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methy-
lene)hydrazinecarboxamide
Methyl hydrazine (41.25 mg, 0.8968 mmoles) was added to ethanolic
solution of 6-(pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde
(100 mg, 0.4484 mmoles) at RT. The reaction mixture was heated at
85.degree. C. for 1.5 hours. The solvent was then evaporated. The
residue was dissolved in ethanol (5 ml), followed by addition of
benzyl isocyanate (140.58 mg, 0.6726 mmoles). The reaction mixture
was refluxed for 2 hours, then the solvent was evaporated. Water
was poured into the residue and the aqueous solution was extracted
with chloroform. Organic layer was separated, washed with water and
brine and dried over sodium sulfate. The crude product was purified
by column chromatography (100-200 mesh size silica gel, 1.5%
methanol in chloroform). Yield: 41%; .sup.1HNMR (DMSO-d.sub.6; 300
MHz): .delta. 9.48 (s, 1H), 9.05 (s, 1H), 8.58 (s, 1H), 8.21 (m,
3H), 7.98 (s, 1H), 7.80 (s, 2H), 7.29 (m, 6H), 4.39 (d, 2H, J=4.2
Hz), 3.35 (s, 3H); MS: m/z 384 (M+1).sup.+.
Example 142
(E)-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene)-N-p-
-tolylhydrazinecarboxamide
The title compound was prepared according to the procedure as set
forth in example 141, except that 1-isocyanato-4-methylbenzene was
used in place of benzyl isocyanate to yield 51% of the title
compound. .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 9.56 (s,
1H), 9.23 (s, 1H), 9.05 (s, 1H), 8.61 (s, 1H), 8.30 (m 3H), 7.84
(s, 1H), 7.49 (m, 3H), 7.11 (d, 1H, J=7.2 Hz), 3.41 (s, 3H), 2.28
(s, 3H); MS: m/z 385 (M+1).sup.+.
Example 143
(E)-N-(2-fluoro-5-methylphenyl)-1-methyl-2-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)hydrazinecarboxamide
The title compound was prepared according to the procedure as set
forth in example 141, except that
1-fluoro-2-isocyanato-4-methylbenzene was used in place of benzyl
isocyanate to yield 35% of the title compound. .sup.1HNMR
(DMSO-d.sub.6; 300 MHz): .delta. 9.46 (s, 1H), 8.99 (d, 2H, J=6.3
Hz), 8.60 (s, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 7.84 (m, 3H), 7.40
(s, 1H), 7.02 (m, 2H), 3.43 (s, 3H), 2.298 (s, 3H); MS: m/z
403(M+1).sup.+.
Example 144
(E)-N-(5-fluoro-2-methylphenyl)-1-methyl-2-((6-(pyridin-3-yl)
imidazo[1,2-a]pyridin-3-yl)methylene)hydrazinecarboxamide
The title compound was prepared according to the procedure as set
forth in example 141, except that
4-fluoro-2-isocyanato-1-methylbenzene was used in place of benzyl
isocyanate to yield 28% of the title compound. .sup.1HNMR
(DMSO-d.sub.6; 300 MHz): .delta. 9.43 (s, 1H), 9.00 (d, 2H, J=19.5
Hz), 8.61 (s, 1H), 8.36 (s, 1H), 8.20 (m, 2H), 7.83 (m, 2H), 7.62
(d, 1H, J=10.5 Hz)), 7.42 (s, 1H), 7.17 (s, 1H), 6.85 (s, 1H), 3.45
(s, 3H), 2.03 (s, 3H); MS: m/z 403(M+1).sup.+.
Example 145
N-benzyl-2-((6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-1-methylhydrazin-
ecarboxamide
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (step 1 of
Intermediate 1, 100 mg, 0.44 mmoles) was dissolved in ethanol
followed by addition of methyl hydrazine (41.25 mg, 0.89 mmoles) at
RT. The reaction mixture was heated at 85.degree. C. for 1.5 hours.
Solvent was evaporated. The residue so obtained was dissolved in
ethanol (5 ml), followed by addition of benzyl isocyanate (140.58
mg, 0.67 mmoles). The reaction was refluxed for 2 hours and then
the solvent was evaporated. Water was poured into the residue and
the aqueous solution was extracted with chloroform. Organic layer
was washed with water and brine, separated and dried over sodium
sulfate. The crude product was purified by column chromatography
(100-200 mesh size silica gel, 1.5% MeOH in CHCl.sub.3). Yield: 70
mg (40.93%); .sup.1HNMR (DMSO-d.sub.6; 300 MHz): .delta. 9.36 (s,
1H), 8.14-8.15 (d, 2H, J=5.4 Hz), 7.93 (bs, 1H), 7.65-7.68 (d, 1H,
J=9 Hz), 7.48-7.51 (d, 1H, J=9 Hz), 7.23-7.35 (m, 5H), 4.39-4.41
(d, 2H, J=5.1 Hz), 3.35 (s, 3H); MS: m/z 386.8(M+1).sup.+.
Example 146
(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-N-(2-fluoro-5-methylphenyl)--
1-methylhydrazinecarboxamide
The title compound was prepared according to the procedure as set
forth in example 145, except that
1-fluoro-2-isocyanato-4-methylbenzene was used in place of benzyl
isocyanate to yield 19.55% of the title compound. .sup.1HNMR
(DMSO-d.sub.6; 500 MHz): .delta. 9.35 (s, 1H), 8.95 (s, 1H), 8.28
(s, 1H), 8.16 (s, 1H), 7.78-7.79 (d, 1H, J=7 Hz), 7.71-7.73 (d, 1H,
J=9.5 Hz), 7.55-7.58 (dd, 1H, J=9.5 Hz, 1.5 Hz), 7.14-7.18 (m, 1H),
6.93-6.94 (m, 1H), 3.42 (s, 3H), 2.30 (s, 3H); MS: m/z
404(M+1).sup.+.
Example 147
(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-N-(5-fluoro-2-methylphenyl)--
1-methylhydrazinecarboxamide
The title compound was prepared according to the procedure as set
forth in example 145, except that
4-fluoro-2-isocyanato-1-methylbenzene was used in place of benzyl
isocyanate to yield 33.52% of the title compound. .sup.1H NMR
(DMSO-d.sub.6; 500 MHz): .delta. 9.36 (s, 1H), 8.86 (s, 1H), 8.27
(s, 1H), 8.14 (s, 1H), 7.67-7.79 (m, 2H), 7.51-7.55 (dd, 1H, J=9.6
Hz, 1.8 Hz), 7.21-7.26 (t, 1H, J=7.8 Hz), 6.81-6.87 (m, 1H), 3.41
(s, 3H), 2.30 (s, 3H); MS: m/z 404 (M+1).sup.+.
Example 148
(E)-1-methyl-N-(2-morpholinoethyl)-2-((6-(pyridin-3-ypimidazo[1,2-a]pyridi-
n-3-yl)methylene)hydrazinecarbothioamide
Methyl hydrazine (41.25 mg, 0.8968 mmoles) was added to ethanolic
solution of 6-(pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde
(100 mg, 0.4484 mmoles) at RT. The reaction mixture was heated at
85.degree. C. for 1.5 hours. The solvent was then evaporated. The
residue was dissolved in ethanol (5 ml), followed by addition of
4-(2-isothiocyanatoethyl) morpholine (114.83 mg, 0.6726 mmoles).
The reaction mixture was refluxed for 2 hours, then the solvent was
evaporated. Water was poured into the residue and the aqueous
solution was extracted with chloroform. Organic layer was
separated, washed with water and brine and dried over sodium
sulfate. The crude product was purified by column chromatography
(100-200 mesh size silica gel, 1.5% MeOH in CHCl.sub.3). Yield:
21%; .sup.1HNMR (CDCl.sub.3; 300 MHz): .delta. 9.39 (s, 1H), 8.91
(s, 1H), 8.71 (s, 1H), 8.11 (m, 3H), 7.93 (m, 1H), 7.67 (d, 1H, J=9
Hz), 7.48 (s, 1H), 4.01 (s, 3H), 3.76 (s, 2H), 3.33 (s, 2H), 2.47
(s, 2H), 2.06 (s, 4H); MS: m/z 424(M+1).sup.+.
Example 149
(E)-N-(4-cyanophenyl)-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-
-yl)methylene)hydrazinecarbothioamide
The title compound was prepared according to the procedure as set
forth in example 148, except that 4-isothiocyanatobenzonitrile was
used in place of 4-(2-isothiocyanatoethyl) morpholine to yield 25%
of the title compound. .sup.1HNMR (CDCl.sub.3; 300 MHz): .delta.
9.77 (s, 1H), 9.29 (s, 1H), 8.87 (s, 1H), 8.17 (s, 1H), 8.20 (d,
2H, J=19.5 Hz), 7.96 (m, 2H), 7.83 (m, 5H), 4.07 (s, 3H); MS: m/z
412 (M+1).sup.+.
Example 150
(E)-N-(4-methoxyphenyl)-1-methyl-2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-
-3-yl)methylene)hydrazinecarbothioamide
The title compound was prepared according to the procedure as set
forth in example 148, except that 1-isothiocyanato-4-methoxybenzene
was used in place of 4-(2-isothiocyanatoethyl)morpholine to yield
25% of the title compound. .sup.1HNMR (CDCl.sub.3; 300 MHz):
.delta. 9.38 (s, 1H), 8.87 (s, 1H), 8.62 (s, 1H), 8.16 (d, 2H,
J=20.7 Hz), 7.92 (d, 1H, J=9.3 Hz), 7.76 (m, 2H), 7.37 (d, 2H,
J=8.1 Hz), 7.11 (s, 1H), 6.92 (d, 2H, J=7.8 Hz), 4.07 (s, 3H), 3.86
(s, 3H); MS: m/z 417(M+1).sup.+.
Example 151
2-((6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-1-methyl-N-(2-morpholinoe-
thyl) hydrazinecarbothioamide
The title compound was prepared according to the procedure as set
forth in example 148, except that
4-(2-isothiocyanatoethyl)morpholine was used in place of benzyl
isocyanate and 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde was
used in place of
6-(pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde to yield 27%
of the title compound. .sup.1HNMR (DMSO-d.sub.6; 300 MHz): .delta.
9.36 (s, 1H), 8.74 (s, 1H), 8.36 (s, 1 Hz), 8.21 (s, 1H), 7.70-7.73
(d, 1H, J=9 Hz), 7.55-7.58 (d, 1H, J=9 Hz), 3.84 (s, 3H), 3.70-3.71
(m, 2H), 3.55 (s, 4H), 2.60 (s, 2H), 2.45 (s, 4H); MS: m/z
425(M+1).sup.+.
Example 152
2-((6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-1-methyl-N-(4-(trifluorom-
ethyl)phenyl) hydrazinecarbothioamide
The title compound was prepared according to the procedure as set
forth in example 148, except that
1-isothiocyanato-4-(trifluoromethyl)benzene was used in place of
benzyl isocyanate and 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde
was used in place of
6-(pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde to yield 35%
of the title compound.
Yield: 35%; .sup.1H NMR (DMSO-d.sub.6; 300 MHz): .delta. 10.58 (s,
1H), 9.48 (s, 1H), 8.51 (s, 1H), 8.33 (s, 1H), 7.93-7.96 (d, 2H,
J=7.8 Hz), 7.73-7.76 (m, 3H), 7.58-7.61 (d, 1H, J=9 Hz), 3.94 (s,
3H); MS: m/z 457(M+2).sup.+.
Pharmacology
The efficacy of the present compounds can be determined by a number
of pharmacological assays well known in the art, such as described
below. The exemplified pharmacological assays, which follow herein
below, have been carried out with the compounds of the present
invention.
Example 153
Protocol for kinase assay (PI3K.alpha.)
The assay was designed as in the reference, Cell, 2006, 125, 733-47
(Supplemental Data), the disclosure of which is incorporated by
reference for the teaching of the assay.
The kinase reaction was carried out in a 25 .mu.L volume in a 1.5
mL microcentrifuge tube. The reaction mixture consisted of kinase
buffer (10 mM Hepes, pH 7.5, 50 mM MgCl.sub.2), 20 ng PI3K.alpha.
kinase (Millipore, USA), 12.5 .mu.g phosphotidylinositol (PI), 10
.mu.M ATP and 1 .mu.Ci .sup.32.gamma. P dATP. Representative
compounds of present invention were added at concentrations (stock
solution was prepared in DMSO and subsequent dilutions were made in
kinase buffer) as mentioned in the table 1. The reactions were
incubated at 30.degree. C. for 20 minutes and were terminated by
adding 1:1 mixture of MeOH and CHCl.sub.3. The tube contents were
mixed on a vortex mixer and centrifuged at 10000 rpm for 2 minutes.
10 .mu.L of the organic (lower) phase was spotted on to a TLC plate
(silica, mobile phase: n-propanol and 2 M glacial acetic acid in
65:35 ratio). The plates were dried and exposed to an X-ray film.
The bands appearing as a result of .sup.32.gamma. P incorporation
in PI were quantitated using the Quantityl)ne (BioRad, USA)
densitometry program. PI-103 (Calbiochem, USA) was used as a
standard.
Results: Table 1 depicts the IC.sub.50 values (.mu.M) of the
representative compounds of present invention for PI3K
inhibition.
TABLE-US-00002 TABLE 1 Example No. IC.sub.50 (.mu.M) Example No.
IC.sub.50 (.mu.M) 5 + 6 + 7 ++ 11 ++ 14 ++ 15 + 16 + 17 ++ 18 ++ 20
++ 21 ++ 22 ++ 23 ++ 25 ++ 26 ++ 27 ++ 84 ++ 100 ++ 115 ++ Standard
80% inhibition PI-103 at 100 nM IC.sub.50 Ranges + 1 .gtoreq.
IC.sub.50 > 0.5 ++ 0.5 .gtoreq. IC.sub.50 > 0.01
Example 154
mTOR Activity Assay
The assay was designed as in the reference, Biochemical Journal,
2000, 350, 717-722, the disclosure of which is incorporated by
reference for the teaching of the assay.
Seed cells (Ovarian cell line A2780, ATCC) were plated in a 96 well
microtitre plate at a density of 50,000 cells/cm.sup.2 in
appropriate complete cell culture medium. The cells were allowed to
adhere for 18-24 hours. The cells were allowed to starve for 24
hours. The cells were pretreated (in triplicates) with the
representative compounds of the present invention (refer table 2a
and 2b) (stock solution was prepared in DMSO and subsequent
dilutions were made in kinase buffer) at a concentration of 10
.mu.M for one hour. Then the cells were stimulated with 20% FCS for
30 minutes. A typical assay would consist of a set of unstimulated
cells, a set of stimulated cells and a set of cells treated with
compounds of present invention and a set of cells treated with the
stimulator. The medium was discarded. The cells were fixed with 100
.mu.L of 3.7% formaldehyde for 15 minutes. The formaldehyde was
discarded by inverting the plate and tapping it on a thick tissue
paper layer to remove traces. The cells were washed and
permeabilized with 200 .mu.L PBS+Triton-X 100 solution (hereafter
referred to as PBS-Triton, containing 0.1% triton-X 100 in
1.times.PBS) three times, incubating the cells each time for 5
minutes. 100 .mu.L blocking solution (10% FCS in PBS-Triton) was
added and incubated for 1 hour at 25.degree. C. The blocking
solution was discarded and cells were incubated with the primary
antibody in PBS-Triton at a dilution of 1:500 for 1 hour at RT
(25.degree. C.). [The primary antibody is Phospho-AKT (Ser 473);
Cell Signaling; Cat. No. 9271]. The primary antibody solution was
discarded and the cells were washed 3 times with PBS-Triton
solution and incubated with the HRP-conjugated secondary antibody
in PBS-Triton at a dilution of 1:500 for 1 hour at RT (25.degree.
C.). The cells were washed 3 times with PBS-Triton followed by two
washes with PBS (to remove traces of triton-X 100). The OPD
(o-phenylene diamine dihydrochloride) substrate was prepared for
detection of the signal by dissolving one tablet set (two tablets)
of SigmaFast OPD (Sigma, Cat No. P9187) in 20 mL distilled water.
It should be protected from light. 100 .mu.L OPD solutions was
added to the wells and the plate was incubated in the dark for 3-5
minutes (depending upon the development of the color). The reaction
was stopped by adding 50 .mu.L 2 N H.sub.2SO.sub.4. The absorbance
was measured at 490 nm. The values were expressed in the treated
samples, in terms of percentage or fold decrease in AKT
phosphorylation with respect to the induced sample. PI-103
(Calbiochem, USA) was used as a standard.
Results: % inhibition of mTOR at 1 .mu.M and 10 .mu.M is indicated
in Table 2a.
IC.sub.50 values of representative compounds for mTOR activity
assay are indicated in Table 2b
TABLE-US-00003 TABLE 2a Example % Inhibition of mTOR Example %
Inhibition of mTOR No. activity at 1 .mu.M No. activity at 1 .mu.M
6 + 7 + 8 + 11 + 15 + 16 + 17 + 20 + 23 + 84 + Standard 50 (PI-103)
% Inhibition of mTOR activity at 10 .mu.M 26 ++ % Inhibition Ranges
+ 50% .gtoreq. % Inhibition .gtoreq. 30% ++ % Inhibition >
50%
TABLE-US-00004 TABLE 2b Example No. mTOR IC.sub.50 (.mu.M) Example
No. mTOR IC.sub.50 (.mu.M) 5 ++ 21 ++ 25 ++ 115 + Standard 50%
inhibition at 1 .mu.M (PI-103) IC.sub.50 Ranges in .mu.M + 10
.gtoreq. IC.sub.50 > 5 ++ 5 .gtoreq. IC.sub.50 .gtoreq. 1
Example 155
Cytotoxicity Assay
Propidium Iodide Assay
The assay was designed as in the reference, Anticancer Drugs, 2002,
13, 1-8, the disclosure of which is incorporated by reference for
the teaching of the assay.
Cells from cell lines as mentioned in the table given below were
seeded at a density of 3000 cells/well in a white opaque 96-well
plate. Following incubation at 37.degree. C./5% CO.sub.2 for a
period of 18-24 hours, the cells were treated with various
concentrations (stock solution was prepared in DMSO and subsequent
dilutions were made in media as per ATCC guidelines) of the
representative compounds of present invention (refer table 3) for a
period of 48 hours. At the end of treatment, the spent culture
medium was discarded, the cells were washed with 1.times.PBS and
200 .mu.l of 7 .mu.g/ml propidium iodide was added to each well.
The plates were frozen at -70.degree. C. for at least 24 hours. For
analysis, the plates were brought to RT, allowed to thaw and were
read in PolarStar fluorimeter with the fluorescence setting. The
percentage of viable cells in the non treated set of wells was
considered to be 100 and the percentage viability following
treatment was calculated accordingly. IC.sub.50 values were
calculated from graphs plotted using these percentages. Results for
representative compounds of present invention in individual cell
lines are shown in Table 3 and 4.
The abbreviations for the Cell Lines as used in Table 3 are:
TABLE-US-00005 Type of Cancer Abbreviation Cell Line Abbreviation
Lung C1 A549 C1a H460 C1b Prostate C2 PC3 C2a Ovarian C3 A2780 C3a
SKOV3 C3b OVCAR 3 C3c Colon C4 HT29 C4a HCT116 C4b Pancreatic C5
PANC 1 C5a CAPAN1 C5b Breast C6 MDA MB 231 C6a MDA MB 468 C6b MCF7
C6c BT 549 C6d T47D C6e Multiple Myeloma C7 U266B1 C7a RPMI 8226
C7b Glioblastoma C8 U 373 C8a U 87 MG C8b Human melanoma C9 G361 C9
Cervical C10 HeLA S3 C10 Hypopharyngeal C11 FaDu C11
TABLE-US-00006 TABLE 3 Example No. Cell Lines 1 2 3 5 6 7 9 10 11
C1 C1a ++ ++ ++ ++ ++ + ++ ++ + C1b ++ ++ ++ -- -- + ++ ++ + C2 C2a
++ ++ ++ -- -- + ++ ++ + C3 C3a ++ ++ ++ ++ ++ -- ++ ++ + C3b -- --
-- ++ -- -- -- -- -- C3c ++ -- ++ ++ ++ -- -- ++ -- C4 C4a -- + --
-- -- -- -- -- -- C4b ++ -- ++ ++ ++ -- -- ++ -- C5 C5a ++ -- -- ++
++ -- -- -- -- C5b ++ -- -- ++ ++ -- -- -- -- C6 C6a -- ++ -- -- --
-- -- -- -- C6b -- -- -- -- -- + ++ -- + C6c -- -- -- -- -- + -- --
-- C6d -- -- -- -- -- -- ++ -- + C6e -- -- -- + + -- -- -- -- C9
C9a -- -- -- -- -- + -- -- -- C11 C11a -- -- -- ++ ++ -- -- -- --
Example No. Cell Lines 12 18 20 21 23 24 25 26 27 C1 C1a ++ + + ++
++ ++ ++ ++ + C1b ++ + + ++ ++ ++ ++ ++ + C2 C2a ++ + + ++ -- ++ ++
-- + C3 C3a ++ -- + ++ ++ ++ ++ ++ -- C3b -- -- -- ++ -- -- ++ ++
-- C3c ++ -- -- ++ -- -- ++ ++ -- C4 C4a -- -- -- -- -- -- -- -- --
C4b ++ -- + ++ -- + ++ -- -- C5 C5a -- -- -- ++ -- -- ++ ++ -- C5b
-- -- -- ++ -- -- ++ ++ -- C6 C6a -- -- -- ++ -- -- ++ -- -- C6b --
+ -- ++ -- -- -- -- + C6c -- + -- ++ -- -- ++ -- + C6d -- -- -- ++
-- -- ++ -- -- C6e -- -- -- -- -- -- ++ -- -- C7 C7a -- -- -- ++ --
-- -- -- -- C7b -- -- -- ++ -- -- -- -- -- C8 C8a -- -- + ++ -- ++
-- -- -- C8b -- -- + ++ -- ++ -- -- -- C9 C9a -- + -- ++ -- -- --
-- + Example No. Cell Lines 28 29 30 31 45 53 54 65 C1 C1a + ++ +
++ ++ ++ ++ ++ C1b + ++ + ++ ++ ++ ++ ++ C2 C2a + ++ + ++ -- -- --
-- C3 C3a + ++ -- ++ -- -- -- -- C3b -- -- -- -- -- -- -- -- C3c --
++ -- -- -- -- -- -- C4 C4a + -- -- + -- -- -- -- C4b -- ++ -- --
-- -- -- -- C5 C5a -- -- -- -- -- -- -- -- C5b -- -- -- -- -- -- --
-- C6 C6a + -- -- ++ -- -- -- -- C6b -- -- + -- -- -- -- -- C6c --
-- + -- -- -- -- -- C9 C9a -- -- + -- -- -- -- -- Example No. Cell
Lines 83 85 88 99 100 132 C1 C1a + ++ ++ ++ ++ ++ C1b + ++ ++ ++ ++
++ C2 C2a + ++ -- ++ -- -- C3 C3a ++ ++ -- ++ ++ -- C3b -- -- -- --
-- -- C3c -- -- -- ++ -- -- C4 C4a + + -- -- -- -- C4b -- -- -- ++
-- -- C5 C5a -- -- -- -- -- -- C5b -- -- -- -- -- -- C6 C6a ++ ++
-- -- -- -- C6b -- -- -- -- -- -- C6c -- -- -- -- -- -- C9 C9a --
-- -- -- -- -- IC.sub.50 Ranges in .mu.M + IC.sub.50 > 5 ++ 5
.gtoreq. IC.sub.50 .gtoreq. 0.01 -- Not Done
TABLE-US-00007 TABLE 4 % inhibition at 1 .mu.M Example No. Cell
Lines 91 142 143 144 146 149 150 152 C2 C2a ++ + + + ++ + + + C3
C3a ++ + + + ++ + + + % Inhibition Ranges + 50% .gtoreq. %
Inhibition .gtoreq. 30% ++ % Inhibition >50%
Example 156
STAT3 Bioassay
Hela STAT3 Assay
Cells were seeded (Hela Stat3-luc, ATCC P/N 30-2002) in a white 96
well plate (Nunc cat.no.136101) at a density of 20,000cells/well in
179 .mu.l volume per well (DMEM from Sigma containing 10% FCS). The
plate was incubated for 24 hours at 37.degree. C./5% CO.sub.2. The
cells (wells in triplicates) were then treated with 1 .mu.l/well of
200.times. stock of the desired compound concentration prepared in
100% DMSO. Curcumin was used as a standard or positive control,
added 10 .mu.g/ml in triplicate. DMSO was used as medium control (1
.mu.l/well added in triplicates). The plate was incubated at
37.degree. C./5% CO.sub.2 for 1 hour. 20 .mu.l/well Oncostatin M
(Oncostatin M, Human, Recombinant, E. coli, Cat.No. 496260, 10
.mu.g from Calbiochem) was added to treated wells, induction
control (in triplicate) (1000 ng/ml stock prepared in serum free
medium to get final concentration 100 ng/ml). The plate was then
incubated for 7-8 hours at 37.degree. C./5% CO.sub.2 for induction.
A typical assay would consist of triplicate of medium control,
triplicate of induction control, triplicate of positive/standard
control and test compounds at desired concentration in triplicates.
For termination Luciferase assay protocol was followed where the
culture medium was removed from all the wells.
Luciferase Assay
200 .mu.l well of PBS was added to remove traces of medium and
compound. The PBS was discarded. 40 .mu.l/well of 1.times. lysis
buffer was added to all the wells. The plate was incubated at RT
for 20 minutes with intermittent shaking. 100 .mu.l/well of LAB
reagent was added to all the wells in dark. {LAB reagent for 1
plate=8 ml Luciferase assay buffer (LAB)+1 ml Coenzyme A (Sigma cat
no. C3019) (2.1 mg/ml stock in LAB)+530 .mu.L of ATP (Sigma
cat.no.A2383) (5.85 mg/ml stock in LAB)+1 ml luciferin reagent
(Promega cat no.245355) (2 mg/ml stock in LAB, protect from
light)}.
The luminescence was immediately read on polar star. The values
were expressed as percentage inhibition, in terms of treated values
to that STAT3 (induction control). IC.sub.50 values were calculated
from graphs using these percentages. Results for representative
compounds of present invention are shown in Table 5.
1.times. Lysis Buffer
TABLE-US-00008 Final concentration Stock Quantity for 100 ml 125 mM
Tris phosphate buffer pH 7.8 0.2M 12.5 ml 10 mM DTT 0.2M 155 mg 50%
glycerol 100% 10 ml 5% Triton X-100 100% 1 ml Distilled water To
make volume 100 ml
1M Tris Phosphate Buffer:
Dissolve 12.114 gm tris(hydroxymethyl)aminomethane (Trizma, Sigma
Aldrich) in 70 ml distilled water and adjust pH to 7.8 using
ortho-phosphoric acid and then make up the volume 100 ml with
distilled water.
Luciferase Assay Buffer
TABLE-US-00009 Final concentration 1000 ml 20 mM Tricine (pH 7.8)
3.58 gm 1.07 mM Mg.cndot.ALBA 520 mg 2.67 mM MgSO.sub.4 657 mg 0.1
mM EDTA 37 mg 33.3 mM DTT 5.1 gm
TABLE-US-00010 TABLE 5 Results for STAT3 activity Example No.
IC.sub.50 (.mu.M) Example No. IC.sub.50 (.mu.M) 1 ++ 2 ++ 4 +++ 5
+++ 6 ++ 8 +++ 9 ++ 10 +++ 13 ++ 14 ++ 15 +++ 16 ++ 20 +++ 21 ++ 22
+++ 24 + 25 +++ 26 +++ 28 + 115 ++ IC.sub.50 Ranges in .mu.M +
IC.sub.50 > 10 ++ 10 .gtoreq. IC.sub.50 > 5 +++ 5 .gtoreq.
IC.sub.50 .gtoreq. 0.1
Example 157
In Vitro Screening to Identify Inhibitors of IL-6 and
TNF-.alpha.
Human Monocyte Assay
The assay was designed as in the reference, Physiol. Res., 2003,
52, 593-598, the disclosure of which is incorporated by reference
for the teaching of the assay.
Peripheral blood mononuclear cells (hPBMC) were harvested from
human blood and suspended in RPMI 1640 culture medium containing
10% FCS, 100 U/mL penicillin and 100 mg/mL streptomycin (assay
medium). Monocytes in the hPBMCs were counted using a Coulter
Counter following which the cells were resuspended at
2.times.10.sup.5 monocytes/mL. A cell suspension containing
2.times.10.sup.4 monocytes was aliquoted per well of a 96-well
plate. Subsequently, the hPBMCs were incubated for 4-5 hours at
37.degree. C., 5% CO.sub.2 (During the incubation, the monocytes
adhered to the bottom of 96-well plastic culture plate). Following
the incubation, the non-adherent lymphocytes were washed with assay
medium and the adherent monocytes re-fed with assay medium. After a
48-hour incubation period (37.degree. C., 5% CO.sub.2), monocytes
were pretreated with various concentrations of representative
compounds of present invention (refer to table 6 and 7) (prepared
in DMSO) or vehicle (0.5% DMSO) for 30 minutes and stimulated with
1 .mu.g/ml LPS (Escherchia coli 0111:B4, Sigma Chemical Co., St.
Louis, Mo.). The incubation was continued for 5 hours at 37.degree.
C., 5% CO.sub.2. Supernatants were harvested, assayed for IL-6 and
TNF-.alpha. by ELISA as described by the manufacturer (BD
Biosciences, USA). Dexamethasone (10 .mu.M) was used as standard
for this assay. The 50% inhibitory concentration (IC.sub.50) values
were calculated by a nonlinear regression method. Biological
results for both IL-6 and TNF.alpha. are indicated in Table 6 and
Table 7 respectively.
TABLE-US-00011 TABLE 6 Example No. IL-6 (IC.sub.50 .mu.M) 1 ++ 2 ++
3 + 4 ++ 5 ++ 6 ++ 9 ++ 10 ++ 11 + 13 ++ 14 ++ 16 ++ 17 ++ 19 ++ 21
++ 22 + 23 ++ 25 ++ 26 ++ 28 ++ 30 + 34 ++ 35 ++ 36 + 39 ++ 40 ++
41 ++ 42 + 43 + 44 ++ 45 ++ 46 + 47 + 50 ++ 51 ++ 52 ++ 53 ++ 54 ++
55 ++ 56 ++ 57 ++ 58 ++ 59 ++ 60 ++ 61 ++ 62 ++ 63 ++ 64 ++ 65 ++
66 ++ 67 ++ 68 ++ 69 ++ 70 ++ 72 + 73 + 74 ++ 84 ++ 87 ++ 88 ++ 99
++ 101 ++ 104 + 105 ++ 106 + 107 ++ 109 + 110 + 112 + 113 ++ 114 +
115 + 117 + 118 + 127 + 128 ++ 129 + 130 ++ 131 + 134 ++ 135 ++ 137
+ 138 + 139 + 141 ++ 142 + 143 ++ 144 + 145 ++ 146 + 148 + 149 +
150 + 151 ++ 152 ++ IC.sub.50 Ranges in .mu.M + IC.sub.50 .gtoreq.
5 ++ 5 > IC.sub.50 .gtoreq. 0.001
TABLE-US-00012 TABLE 7 Example No. TNF-.alpha. Example No. TNF-
.alpha. 1 ++ 4 ++ 5 + 6 ++ 10 ++ 13 ++ 14 ++ 16 ++ 19 ++ 21 ++ 45
++ 105 ++ IC.sub.50 Ranges in .mu.M + 15 .gtoreq. IC.sub.50 > 1
++ 1 .gtoreq. IC.sub.50 > 0.001
Example 158
Inhibition of Production of Cytokines
Synovial Tissue Assay
The assay was designed as in the reference, Lancet, 2(8657), 244-7,
Jul. 29 (1989), the disclosure of which is incorporated by
reference for the teaching of the assay.
Stock Solution: Compounds of the present invention were dissolved
in DMSO to obtain a stock solution of 20 mM.
Synovial tissue was obtained from rheumatoid arthritis patients
undergoing knee replacement surgery. The tissue was minced into
small pieces and digested in RPMI medium containing 100 U/ml
penicillin-G, 100 .mu.g/ml streptomycin, 50 ng/ml amphotericin B
(GIBCO; USA), 1.33 mg/ml collagenase Type I (Worthington
Biochemical Corporation, New Jersey), 0.5 .mu.g/ml DNAse Type I
(Sigma Aldrich; St. Louis, Mo.) and 8.33 U/ml heparin (Biological
E. Limited, India) for 3 hours at 37.degree. C., 5% CO.sub.2. The
digested tissue was filtered through a membrane (mesh size 70
micron; Sigma Aldrich). Subsequently, the cells were washed 3 times
and resuspended in complete medium (RPMI supplemented with 5% FBS
and 5% human serum-AB+) at a concentration of 1.times.10.sup.6
cells/ml. All cell washes in this assay were performed using
Rosewall Park Memorial Institute (RPMI)-1640 medium (JRH;
Australia). For the experiment, 100 .mu.l of cell suspension was
added to the wells of a 96-well culture plate. Following cell
plating, 100 .mu.l of the culture medium and 1 .mu.l of various
concentrations (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 and 100 .mu.M)
of the compounds of present invention dissolved in DMSO were added
to the cells. The final concentration of DMSO was adjusted to 0.5%.
For experimental purposes, 1 .mu.l of 20.times. concentrated
solution of the compounds of present invention were dissolved in
200 .mu.l cell suspension to achieve a final concentration of 0.01,
0.03, 0.1, 0.3, 1, 3, 10, 30 and 100 .mu.M. The vehicle (0.5% DMSO)
was used as control. 10 .mu.M dexamethasone (Sigma Aldrich) or 1
.mu.M 7-hydroxyfluorinide (7HF) were used as standards for the
experiments. The plates were incubated for 16 hours at 37.degree.
C., 5% CO.sub.2. Subsequently, the supernatants were harvested and
stored at -70.degree. C. The amounts of TNF-.alpha., IL-6 and
interleukin-8 (IL-8) in the supernatants were assayed using OptiEIA
ELISA sets, (BD BioSciences Pharmingen). The protocol followed was
as per manufacturers instructions. The 50% inhibitory concentration
(IC.sub.50) values were calculated by a nonlinear regression method
using the GraphPad software (Prism 3.03). The cytotoxicity of test
compounds in synovial cells was assessed by MTS assay. Absorbance
was measured at 490 nm. Percent cytotoxicity was calculated by the
equation: % Cytotoxicity=(A-B)/A.times.100 where, A is the
absorbance of cells treated with DMSO alone and B is the absorbance
of cells treated with the test article. Results: Compounds of the
present invention inhibited the spontaneous production of IL-6
and/or TNF-.alpha. and/or IL-.beta. and/or IL-8 from freshly
isolated synovial tissue cells from rheumatoid arthritis patients.
The IC.sub.50 of IL-6, TNF-.alpha. and IL-8 inhibition are provided
in the Table 8.
TABLE-US-00013 TABLE 8 Example Synovial tissue (IC.sub.50 .mu.M)
No. IL-6 TNF-.alpha. IL-8 4 ++ ++ + 5 ++ ++ + 6 + ++ + 9 ++ ++ + 13
++ ++ + 14 ++ ++ + 16 ++ ++ + 19 + + + 21 ++ ++ ++ 25 ++ ++ +
IC.sub.50 Ranges in .mu.M + 3 .gtoreq. IC.sub.50 > 0.3 ++ 0.3
.gtoreq. IC.sub.50 > 0.01
In-Vivo Studies
All experiments were carried out in accordance with the guidelines
of the Committee for the Purpose of Control and Supervision of
Experiments on Animals (CPCSEA), Tamil Nadu, India. Procedures
using laboratory animals were approved by the Institutional Animal
Ethics Committee (IAEC) of Piramal Life Sciences Limited, Mumbai,
India.
Example 159
Ulcerative Colitis
The efficacy of compounds of the present invention on the gross
pathology of colitis and proinflammatory mediators was determined
by following the method described in Am. J. Physiol. Gastrointest.
Liver Physiol. 295 (6): G1237-45 (2008), the disclosure of which is
incorporated by reference for the teaching of the assay.
Induction of Colitis
C57BL/6J mice (6 weeks of age, weighing 18-22 gms) were obtained
from Jackson Laboratories (Bar Harbor, Me.) and housed in
individually ventilated cage (IVC) system. Colitis was induced in
mice by replacing drinking water with 3% (w/v) DSS (molecular
weight 35-50 kDa, ICN Biomedicals, Aurora, Ohio, US) in water. This
solution was made available to the experimental animals ad libitum,
from day 0 to day 10. A batch of six nai{umlaut over (v)}e animals
received water instead of DSS during this period.
DSS-induction of colitis was manifested with increase in clinical
disease activity index associated with weight loss and presence of
blood in feces.
Treatment
The animals were weighed every day and the record of body weights
was maintained. The compound of Example 25 (10 mg/kg, prepared at a
concentration of 1 mg/mL in 0.5% (w/v) CMC after mixing a drop of
Tween 20) was administered orally daily to the colitis induced
animals. This treatment was initiated on day 6 and continued up to
day 10. During this period, DSS control animals received DSS,
positive control animals received 5-aminosalicylic acid (5-ASA, 25
mg/kg, p.o.) and naive animals received 0.5% CMC once daily.
Evaluation:
At the end of DSS treatment period, mice were humanely euthanized
with 15% urethane (i.p.). The whole colon (i.e., including ceacum,
proximal colon and distal colon) was excised.
The colon was macrosopically assessed by determining a) Rectal
bleeding/blood in faeces b) Stool consistency c) Blood in colon d)
Colon length e) % weight loss f) Blood hemoglobin concentration
Disease Activity Index: various features were scored as delineated
in the following table.
Disease activity index is the sum of scores of all features.
TABLE-US-00014 Feature scored Score Description % Weight loss 0 No
change/increase 1 0-5% Reduction 2 5-10% Reduction 3 10-15%
Reduction 4 10-20% Reduction Rectal Bleeding 0 Absent 1 Slightly
present 2 Heavy Stool Consistency 0 Normal 1 Slightly loose 2 Loose
3 Diarrhoea Blood in Colon 0 Absent 1 Slightly present 2 Markedly
present
Results: 1. DSS-induction of colitis was manifested with
significant increase in clinical disease activity index associated
with weight loss, decrease in colon length, reduction in
hematocrit, increased rectal bleeding, increase in colon blood and
loose stools (FIGS. 1-6). 2. Compound of Example 25 attenuated
DSS-induced body weight loss (FIG. 1) 3. Compound of Example 25
inhibited DSS-induced (i) shortening of colon, and (ii) decrease in
hematocrit (FIGS. 2 and 3) 4. Compound of Example 25 improved
rectal bleeding index (FIG. 4) 5. Compound of Example 25 attenuated
the DSS-induced colon bleeding (FIG. 5) 6. Compound of Example 25
reduced DSS-induced disease activity index (FIG. 6)
It should be noted that, as used in this specification and the
appended claims, the singular forms "a", "an", and "the" include
plural referents unless the content clearly dictates otherwise.
Thus, for example, reference to a composition containing "a
compound" includes a mixture of two or more compounds. It should
also be noted that the term "or" is generally employed in its sense
including "and/or" unless the content clearly dictates
otherwise.
All publications and patent applications in this specification are
indicative of the level of ordinary skill in the art to which this
invention pertains.
The invention has been described with reference to various specific
and preferred embodiments and techniques. However, it should be
understood that many variations and modifications may be made while
remaining within the spirit and scope of the invention.
* * * * *